Acta Crystallographica Section A Foundations of Crystallography, 1984
i~orphous replacement and anamolous scattering from a single mercuric iodide derivative (Freymann... more i~orphous replacement and anamolous scattering from a single mercuric iodide derivative (Freymann, Netcalf, Turner and ~1iley I unpublished). The electron density map indicates a rod-shaped dimer, with a core of four 80 ~ long alpha-helices. The human histocompatability antigen F~~-A2 is active in tissue graft rejec~ion and iMuUTIological recognition during surveillance by "T-killerl! cells. The papainsolubilized HL~ is a 2 chain structure (46,000 daltons)r which is purified from human tissue culture cells. This is a technically challenging problem as the prystals are very thin plates. X-ray data to 2.8 g resolution for t..i-Ie native and a platinum tetrachloride derivative were collected at the ErffiL synchrotron outstation in Hamburg from crystals 10-30 microns thick. Three platinQ~ sites have been determined from the three-dimensional difference Patterson (Bjorkman t Bennett and \,iley, unpublished). F_'1 antigenic ally distinct BLAt A28 t forms an isomorphous crystal. Further progress in this analysis \.;ill be discussed. 02. X-8 THE STRUCTURE OF NEURAHINIDASE.
Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty... more Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty acids. Because these fatty acids are primarily provided by diet, FAS is normally expressed at low levels; however, it is highly up-regulated in many cancers. Human enoyl-acyl carrier protein-reductase (hER) is one of the FAS catalytic domains, and its inhibition by drugs like triclosan (TCL) can increase cytotoxicity and decrease drug resistance in cancer cells. We have determined the structure of hER in the presence and absence of TCL. TCL was not bound in the active site, as predicted, but rather at the protein-protein interface (PPI). TCL binding induces a dimer orientation change that causes downstream structural rearrangement in critical active site residues. Kinetics studies indicate that TCL is capable of inhibiting the isolated hER domain with an IC50 of ∼ 55 μM. Given the hER-TCL structure and the inhibition observed in the hER domain, it seems likely that TCL is observed in th...
The refined 1.9-A resolution structure of the periplasmic D-galactose-binding protein (GBP) revea... more The refined 1.9-A resolution structure of the periplasmic D-galactose-binding protein (GBP) reveals a calcium ion surrounded by seven ligands, all protein oxygen atoms. A nine-residue loop (amino-acid positions 134-142), which is preceded by a beta-turn and followed by a beta-strand, provides five ligands from every second residue. The last two ligands are supplied by the carboxylate group of Glu 205. The entire GBP Ca2+-binding site adopts a conformation very similar to the site in the 'helix-loop-helix' or 'EF-hand' unit commonly found in intracellular calcium-binding proteins, but without the two helices. Structural analyses have also uncovered the sugar-binding site some 30 A from the calcium and a site for interacting with the membrane-bound trg chemotactic signal transducer approximately 45 A from the calcium. Our results show that a common tight calcium binding site of ancient origin can be tethered to different secondary structures. They also provide the first demonstration of a metal-binding site in a protein which is involved in bacterial active transport and chemotaxis.
In the course of refining crystallographically the crystal structure of the D-galactose/ D-glucos... more In the course of refining crystallographically the crystal structure of the D-galactose/ D-glucose-binding protein (Gal/GlcBP)1 at 1.9 A resolution, we discovered a bound calcium (Vyas et al. 1987). The Gal/GlcBP is a member of a family of proteins (collectively called “binding proteins” which are located in the periplasmic space of Gram-negative bacteria. All binding proteins (~2 dozen) serve as initial receptors for the high-affinity active transport systems for a variety of amino acids, dipeptides, carbohydrates, and oxyanions (for recent reviews see Furlong 1987). Moreover, four of these proteins also act as receptors for bacterial chemotaxis (Macnab 1987). Each process further requires protein components lodged in the cytoplasmic membrane. The membrane components for active transport are the ones actually responsible in translocating nutrients from the periplasm to the cytoplasm. Translocation is triggered presumably by the interaction of the substrate-loaded binding proteins and each corresponding membrane component. On the other hand, the interaction between binding protein and transmembrane signal transducer proteins, the membrane components for chemotaxis, trigger taxis toward chemical attractants.
for an ABC-type phosphate transport system in gramnegative bacteria, a similar role of PstS-1 in ... more for an ABC-type phosphate transport system in gramnegative bacteria, a similar role of PstS-1 in M. tuberculosis was proposed (Andersen, 1994). Indeed, we have shown that purified recombinant PstS-1 does bind phosphate (Pi) with very similar affinity (in the low micromolar
Mammalian formiminotransferase cyclodeaminase (FTCD), a 0.5 million Dalton homo-octameric enzyme,... more Mammalian formiminotransferase cyclodeaminase (FTCD), a 0.5 million Dalton homo-octameric enzyme, plays important roles in coupling histidine catabolism with folate metabolism and integrating the Golgi complex with the vimentin intermediate filament cytoskeleton. It is also linked to two human diseases, autoimmune hepatitis and glutamate formiminotransferase deficiency. Determination of the FTCD structure by X-ray crystallography and electron cryomicroscopy revealed that the eight subunits, each composed of distinct FT and CD domains, are arranged like a square doughnut. A key finding indicates that coupling of three subunits governs the octamer-dependent sequential enzyme activities, including channeling of intermediate and conformational change. The structure further shed light on the molecular nature of two strong antigenic determinants of FTCD recognized by autoantibodies from patients with autoimmune hepatitis and on the binding of thin vimentin filaments to the FTCD octamer.
Proceedings of the National Academy of Sciences, 1983
X-ray diffraction studies of a D-galactose-binding protein essential for transport and chemotaxis... more X-ray diffraction studies of a D-galactose-binding protein essential for transport and chemotaxis in Escherichia coli have yielded a model of the polypeptide chain backbone. An initial polyalanine backbone trace was obtained at 3.2 A resolution by the molecular replacement technique, using a polyalanine search model derived from the refined structure of the L-arabinose-binding protein. Concurrently, a 3 A resolution electron-density map of the D-galactose receptor was determined from multiple isomorphous replacement (MIR) phases. The properly transformed initial polyalanine model superimposed on the MIR electron-density map proved to be an excellent guide in obtaining a final trace. The few changes made in the polyalanine model to improve the fit to the density were confined primarily to the COOH-terminal peptide and some loops connecting the elements of the secondary structure. Despite the lack of significant sequence homology, the overall course of the polypeptide backbone of the ...
Proceedings of the National Academy of Sciences, 2003
The structure of a complex between the Fab fragment of the antibody (SYA/J6) specific for the cel... more The structure of a complex between the Fab fragment of the antibody (SYA/J6) specific for the cell surface O-antigen polysaccharide of the pathogenShigella flexneriY and an octapeptide (Met–Asp–Trp–Asn–Met–His–Ala–Ala), a functional mimic of the O-antigen, has been determined at 1.8-Å resolution. Comparison of the structure with that of the complex with the pentasaccharide antigen [→2)-α-l-Rha-(1→2)-α-l-Rha-(1→3)-α-l-Rha-(1→3)-β-d-GlcNAc-(1→2)-α-l-Rha-(1→] reveals the molecular recognition process by which a peptide mimics a carbohydrate in binding to an antibody. The binding modes of the two ligands differ considerably. Octapeptide binding complements the shape of the combining site groove much better than pentasaccharide binding. Moreover, the peptide makes a much greater number of contacts (126), which are mostly van der Waals interactions, with the Fab than the saccharide (74). An unusual feature is also the involvement of 12 water molecules in mediating hydrogen bonds between r...
Proceedings of the National Academy of Sciences, 2007
Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins ... more Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins in x-ray crystallographic refinement. The foundation for this protocol is a recently developed elastic normal mode analysis that produces much more accurate eigenvectors without the tip effect. The effectiveness of the procedure is demonstrated on the refinement of a 3.42-Å structure of formiminotransferase cyclodeaminase, a 0.5-MDa homooctameric enzyme. Using an order of magnitude fewer adjustable thermal parameters than the conventional isotropic refinement, this protocol resulted in a decrease of the values of R cryst and R free and improvements of the density map. Several poorly resolved regions in the original isotropically refined structure became clearer so that missing side chains were fitted easily and mistraced backbone was corrected. Moreover, the distribution of anisotropic thermal ellipsoids revealed functionally important structure flexibility. This normal-mode-based refine...
Electrostatic interactions are of considerable importance in protein structure and function, and ... more Electrostatic interactions are of considerable importance in protein structure and function, and in a variety of cellular and biochemical processes. Here we report three similar findings from highly refined atomic structures of periplasmic binding proteins. Hydrogen bonds, acting primarily through backbone peptide units, are mainly responsible for the involvement of the positively charged arginine 151 residue in the ligand site of the arabinose-binding protein, for the association between teh sulphate-binding protein and the completely buried sulphate dianion, and for the formation of the complex of the leucine/isoleucine/valine-binding protein with the leucine zwitterion. We propose a general mechanism in which the isolated charges on the various buried, desolvated ionic groups are stabilized by the polarized peptide units. This mechanism also has broad application to processes requiring binding of uncompensated ions and charged ligands and stabilization of enzyme reaction charged intermediates, as well as activation of catalytic residues.
The publisher regrets that Table 1 was inadvertently omitted from the final version of the manusc... more The publisher regrets that Table 1 was inadvertently omitted from the final version of the manuscript. On page 15, section I cyt crystal structure, the first sentence incorrectly refers to Table S1 when it should have referred to Table 1. For the reader's convenience, the corrected sentence along with Table 1 appears below. The recombinant M. ruber I cyt (residues 1-344) was obtained, and its crystal structure was determined by single-wavelength anomalous dispersion technique and refined to 2.6 Å resolution (see Supplementary Methods and Table 1). a Data collected at APS beam line 19ID. I222 space group with one molecule in the asymmetric unit and unit cell dimensions of a = 76.32 Å, b = 102.18 Å, c = 139.06 Å, and α = β = γ = 90°. Both native and SAD crystals are isomorphous. The solvent content and Matthew's coefficient (V M) were calculated to be 64.2% and 3.44 Å 3 /Da, respectively. b Values in parenthesis are for the highest-resolution shell.
The antigenic recognition of Shigella flexneri O-polysaccharide, which consists of a repeating un... more The antigenic recognition of Shigella flexneri O-polysaccharide, which consists of a repeating unit ABCD [f2)-R-L-Rhap-(1f2)-R-L-Rhap-(1f3)-R-L-Rhap-(1f3)-D-GlcpNAc-(1f], by the monoclonal antibody SYA/J6 (IgG3, κ) has been investigated by crystallographic analysis of the Fab domain and its two complexes with two antigen segments (a pentasaccharide Rha A-Rha B-Rha C-GlcNAc D-Rha A′ and a modified trisaccharide Rha B-Rha C*-GlcNAc D in which Rha C* is missing a C2-OH group). These complex structures, the first for a Fab specific for a periodic linear heteropolysaccharide, reveal a binding site groove (between the V H and V L domains) that makes polar and nonpolar contacts with all the sugar residues of the pentasaccharide. Both main-chain and side-chain atoms of the Fab are used in ligand binding. The charged side chain of Glu H50 of CDR H2 forms crucial hydrogen bonds to GlcNAc of the oligosaccharides. The modified trisaccharide is more buried and fits more snugly than the pentasaccharide. It also makes as many contacts (∼75) with the Fab as the pentasaccharide, including the same number of hydrogen bonds (eight, with four being identical). It is further engaged in more hydrophobic interactions than the pentasaccharide. These three features favorable to trisaccharide binding are consistent with the observation of a tighter complex with the trisaccharide than the pentasaccharide. Thermodynamic data demonstrate that the native tri-to pentasaccharides have free energies of binding in the range of 6.8-7.4 kcal mol-1 , and all but one of the hydrogen bonds to individual hydroxyl groups provide no more than ∼0.7 kcal mol-1. They further indicate that hydrophobic interactions make significant contributions to binding and, as the native epitope becomes larger across the tri-, tetra-, pentasaccharide series, entropy contributions to the free energy become dominant. † This work was supported by grants from NIH (AI 40061 to N.K.V., and GM 21371 to F.A.Q.) and the Welch Foundation (to F.A.Q), the Natural Sciences and Engineering Research Council of Canada (NSERC) (to D.R.B. and B.M.P), and an NSERC postgraduate fellowship (to M.A.J.). F.A.Q. is Investigator in the Howard Hughes Medical Institute. ‡ The atomic coordinates have been deposited in the Protein Data Bank (accession numbers 1M71, 1M7D, and 1M7I).
Acta Crystallographica Section A Foundations of Crystallography, 1984
i~orphous replacement and anamolous scattering from a single mercuric iodide derivative (Freymann... more i~orphous replacement and anamolous scattering from a single mercuric iodide derivative (Freymann, Netcalf, Turner and ~1iley I unpublished). The electron density map indicates a rod-shaped dimer, with a core of four 80 ~ long alpha-helices. The human histocompatability antigen F~~-A2 is active in tissue graft rejec~ion and iMuUTIological recognition during surveillance by "T-killerl! cells. The papainsolubilized HL~ is a 2 chain structure (46,000 daltons)r which is purified from human tissue culture cells. This is a technically challenging problem as the prystals are very thin plates. X-ray data to 2.8 g resolution for t..i-Ie native and a platinum tetrachloride derivative were collected at the ErffiL synchrotron outstation in Hamburg from crystals 10-30 microns thick. Three platinQ~ sites have been determined from the three-dimensional difference Patterson (Bjorkman t Bennett and \,iley, unpublished). F_'1 antigenic ally distinct BLAt A28 t forms an isomorphous crystal. Further progress in this analysis \.;ill be discussed. 02. X-8 THE STRUCTURE OF NEURAHINIDASE.
Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty... more Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty acids. Because these fatty acids are primarily provided by diet, FAS is normally expressed at low levels; however, it is highly up-regulated in many cancers. Human enoyl-acyl carrier protein-reductase (hER) is one of the FAS catalytic domains, and its inhibition by drugs like triclosan (TCL) can increase cytotoxicity and decrease drug resistance in cancer cells. We have determined the structure of hER in the presence and absence of TCL. TCL was not bound in the active site, as predicted, but rather at the protein-protein interface (PPI). TCL binding induces a dimer orientation change that causes downstream structural rearrangement in critical active site residues. Kinetics studies indicate that TCL is capable of inhibiting the isolated hER domain with an IC50 of ∼ 55 μM. Given the hER-TCL structure and the inhibition observed in the hER domain, it seems likely that TCL is observed in th...
The refined 1.9-A resolution structure of the periplasmic D-galactose-binding protein (GBP) revea... more The refined 1.9-A resolution structure of the periplasmic D-galactose-binding protein (GBP) reveals a calcium ion surrounded by seven ligands, all protein oxygen atoms. A nine-residue loop (amino-acid positions 134-142), which is preceded by a beta-turn and followed by a beta-strand, provides five ligands from every second residue. The last two ligands are supplied by the carboxylate group of Glu 205. The entire GBP Ca2+-binding site adopts a conformation very similar to the site in the 'helix-loop-helix' or 'EF-hand' unit commonly found in intracellular calcium-binding proteins, but without the two helices. Structural analyses have also uncovered the sugar-binding site some 30 A from the calcium and a site for interacting with the membrane-bound trg chemotactic signal transducer approximately 45 A from the calcium. Our results show that a common tight calcium binding site of ancient origin can be tethered to different secondary structures. They also provide the first demonstration of a metal-binding site in a protein which is involved in bacterial active transport and chemotaxis.
In the course of refining crystallographically the crystal structure of the D-galactose/ D-glucos... more In the course of refining crystallographically the crystal structure of the D-galactose/ D-glucose-binding protein (Gal/GlcBP)1 at 1.9 A resolution, we discovered a bound calcium (Vyas et al. 1987). The Gal/GlcBP is a member of a family of proteins (collectively called “binding proteins” which are located in the periplasmic space of Gram-negative bacteria. All binding proteins (~2 dozen) serve as initial receptors for the high-affinity active transport systems for a variety of amino acids, dipeptides, carbohydrates, and oxyanions (for recent reviews see Furlong 1987). Moreover, four of these proteins also act as receptors for bacterial chemotaxis (Macnab 1987). Each process further requires protein components lodged in the cytoplasmic membrane. The membrane components for active transport are the ones actually responsible in translocating nutrients from the periplasm to the cytoplasm. Translocation is triggered presumably by the interaction of the substrate-loaded binding proteins and each corresponding membrane component. On the other hand, the interaction between binding protein and transmembrane signal transducer proteins, the membrane components for chemotaxis, trigger taxis toward chemical attractants.
for an ABC-type phosphate transport system in gramnegative bacteria, a similar role of PstS-1 in ... more for an ABC-type phosphate transport system in gramnegative bacteria, a similar role of PstS-1 in M. tuberculosis was proposed (Andersen, 1994). Indeed, we have shown that purified recombinant PstS-1 does bind phosphate (Pi) with very similar affinity (in the low micromolar
Mammalian formiminotransferase cyclodeaminase (FTCD), a 0.5 million Dalton homo-octameric enzyme,... more Mammalian formiminotransferase cyclodeaminase (FTCD), a 0.5 million Dalton homo-octameric enzyme, plays important roles in coupling histidine catabolism with folate metabolism and integrating the Golgi complex with the vimentin intermediate filament cytoskeleton. It is also linked to two human diseases, autoimmune hepatitis and glutamate formiminotransferase deficiency. Determination of the FTCD structure by X-ray crystallography and electron cryomicroscopy revealed that the eight subunits, each composed of distinct FT and CD domains, are arranged like a square doughnut. A key finding indicates that coupling of three subunits governs the octamer-dependent sequential enzyme activities, including channeling of intermediate and conformational change. The structure further shed light on the molecular nature of two strong antigenic determinants of FTCD recognized by autoantibodies from patients with autoimmune hepatitis and on the binding of thin vimentin filaments to the FTCD octamer.
Proceedings of the National Academy of Sciences, 1983
X-ray diffraction studies of a D-galactose-binding protein essential for transport and chemotaxis... more X-ray diffraction studies of a D-galactose-binding protein essential for transport and chemotaxis in Escherichia coli have yielded a model of the polypeptide chain backbone. An initial polyalanine backbone trace was obtained at 3.2 A resolution by the molecular replacement technique, using a polyalanine search model derived from the refined structure of the L-arabinose-binding protein. Concurrently, a 3 A resolution electron-density map of the D-galactose receptor was determined from multiple isomorphous replacement (MIR) phases. The properly transformed initial polyalanine model superimposed on the MIR electron-density map proved to be an excellent guide in obtaining a final trace. The few changes made in the polyalanine model to improve the fit to the density were confined primarily to the COOH-terminal peptide and some loops connecting the elements of the secondary structure. Despite the lack of significant sequence homology, the overall course of the polypeptide backbone of the ...
Proceedings of the National Academy of Sciences, 2003
The structure of a complex between the Fab fragment of the antibody (SYA/J6) specific for the cel... more The structure of a complex between the Fab fragment of the antibody (SYA/J6) specific for the cell surface O-antigen polysaccharide of the pathogenShigella flexneriY and an octapeptide (Met–Asp–Trp–Asn–Met–His–Ala–Ala), a functional mimic of the O-antigen, has been determined at 1.8-Å resolution. Comparison of the structure with that of the complex with the pentasaccharide antigen [→2)-α-l-Rha-(1→2)-α-l-Rha-(1→3)-α-l-Rha-(1→3)-β-d-GlcNAc-(1→2)-α-l-Rha-(1→] reveals the molecular recognition process by which a peptide mimics a carbohydrate in binding to an antibody. The binding modes of the two ligands differ considerably. Octapeptide binding complements the shape of the combining site groove much better than pentasaccharide binding. Moreover, the peptide makes a much greater number of contacts (126), which are mostly van der Waals interactions, with the Fab than the saccharide (74). An unusual feature is also the involvement of 12 water molecules in mediating hydrogen bonds between r...
Proceedings of the National Academy of Sciences, 2007
Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins ... more Here we report a normal-mode-based protocol for modeling anisotropic thermal motions of proteins in x-ray crystallographic refinement. The foundation for this protocol is a recently developed elastic normal mode analysis that produces much more accurate eigenvectors without the tip effect. The effectiveness of the procedure is demonstrated on the refinement of a 3.42-Å structure of formiminotransferase cyclodeaminase, a 0.5-MDa homooctameric enzyme. Using an order of magnitude fewer adjustable thermal parameters than the conventional isotropic refinement, this protocol resulted in a decrease of the values of R cryst and R free and improvements of the density map. Several poorly resolved regions in the original isotropically refined structure became clearer so that missing side chains were fitted easily and mistraced backbone was corrected. Moreover, the distribution of anisotropic thermal ellipsoids revealed functionally important structure flexibility. This normal-mode-based refine...
Electrostatic interactions are of considerable importance in protein structure and function, and ... more Electrostatic interactions are of considerable importance in protein structure and function, and in a variety of cellular and biochemical processes. Here we report three similar findings from highly refined atomic structures of periplasmic binding proteins. Hydrogen bonds, acting primarily through backbone peptide units, are mainly responsible for the involvement of the positively charged arginine 151 residue in the ligand site of the arabinose-binding protein, for the association between teh sulphate-binding protein and the completely buried sulphate dianion, and for the formation of the complex of the leucine/isoleucine/valine-binding protein with the leucine zwitterion. We propose a general mechanism in which the isolated charges on the various buried, desolvated ionic groups are stabilized by the polarized peptide units. This mechanism also has broad application to processes requiring binding of uncompensated ions and charged ligands and stabilization of enzyme reaction charged intermediates, as well as activation of catalytic residues.
The publisher regrets that Table 1 was inadvertently omitted from the final version of the manusc... more The publisher regrets that Table 1 was inadvertently omitted from the final version of the manuscript. On page 15, section I cyt crystal structure, the first sentence incorrectly refers to Table S1 when it should have referred to Table 1. For the reader's convenience, the corrected sentence along with Table 1 appears below. The recombinant M. ruber I cyt (residues 1-344) was obtained, and its crystal structure was determined by single-wavelength anomalous dispersion technique and refined to 2.6 Å resolution (see Supplementary Methods and Table 1). a Data collected at APS beam line 19ID. I222 space group with one molecule in the asymmetric unit and unit cell dimensions of a = 76.32 Å, b = 102.18 Å, c = 139.06 Å, and α = β = γ = 90°. Both native and SAD crystals are isomorphous. The solvent content and Matthew's coefficient (V M) were calculated to be 64.2% and 3.44 Å 3 /Da, respectively. b Values in parenthesis are for the highest-resolution shell.
The antigenic recognition of Shigella flexneri O-polysaccharide, which consists of a repeating un... more The antigenic recognition of Shigella flexneri O-polysaccharide, which consists of a repeating unit ABCD [f2)-R-L-Rhap-(1f2)-R-L-Rhap-(1f3)-R-L-Rhap-(1f3)-D-GlcpNAc-(1f], by the monoclonal antibody SYA/J6 (IgG3, κ) has been investigated by crystallographic analysis of the Fab domain and its two complexes with two antigen segments (a pentasaccharide Rha A-Rha B-Rha C-GlcNAc D-Rha A′ and a modified trisaccharide Rha B-Rha C*-GlcNAc D in which Rha C* is missing a C2-OH group). These complex structures, the first for a Fab specific for a periodic linear heteropolysaccharide, reveal a binding site groove (between the V H and V L domains) that makes polar and nonpolar contacts with all the sugar residues of the pentasaccharide. Both main-chain and side-chain atoms of the Fab are used in ligand binding. The charged side chain of Glu H50 of CDR H2 forms crucial hydrogen bonds to GlcNAc of the oligosaccharides. The modified trisaccharide is more buried and fits more snugly than the pentasaccharide. It also makes as many contacts (∼75) with the Fab as the pentasaccharide, including the same number of hydrogen bonds (eight, with four being identical). It is further engaged in more hydrophobic interactions than the pentasaccharide. These three features favorable to trisaccharide binding are consistent with the observation of a tighter complex with the trisaccharide than the pentasaccharide. Thermodynamic data demonstrate that the native tri-to pentasaccharides have free energies of binding in the range of 6.8-7.4 kcal mol-1 , and all but one of the hydrogen bonds to individual hydroxyl groups provide no more than ∼0.7 kcal mol-1. They further indicate that hydrophobic interactions make significant contributions to binding and, as the native epitope becomes larger across the tri-, tetra-, pentasaccharide series, entropy contributions to the free energy become dominant. † This work was supported by grants from NIH (AI 40061 to N.K.V., and GM 21371 to F.A.Q.) and the Welch Foundation (to F.A.Q), the Natural Sciences and Engineering Research Council of Canada (NSERC) (to D.R.B. and B.M.P), and an NSERC postgraduate fellowship (to M.A.J.). F.A.Q. is Investigator in the Howard Hughes Medical Institute. ‡ The atomic coordinates have been deposited in the Protein Data Bank (accession numbers 1M71, 1M7D, and 1M7I).
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