Multiple Modes of Binding Enhance the Affinity of DC-SIGN for High Mannose N-Linked Glycans Found on Viral Glycoproteins
The dendritic cell surface receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR specifically recognize high mannose N-linked carbohydrates on viral pathogens. Previous studies have shown that these receptors bind the outer trimannose branch Manα1-3[Manα1-6]Manα present in high mannose structures. Although the trimannoside binds to DC-SIGN or DC-SIGNR more strongly than mannose, additional affinity enhancements are observed in the presence of one or more Manα1-2Manα moieties on the nonreducing termini of oligomannose structures. The molecular basis of this enhancement has been investigated by determining crystal structures of DC-SIGN bound to a synthetic six-mannose fragment of a high mannose N-linked oligosaccharide, Manα1-2Manα1-3[Manα1-2Manα1-6]Manα1-6Man and to the disaccharide Manα1-2Man. The structures reveal mixtures of two binding modes in each case. Each mode features typical C-type lectin binding at the principal Ca2+-binding site by one mannose residue. In addition, other sugar residues form contacts unique to each binding mode. These results suggest that the affinity enhancement displayed toward oligosaccharides decorated with the Manα1-2Manα structure is due in part to multiple binding modes at the primary Ca2+ site, which provide both additional contacts and a statistical (entropic) enhancement of binding. The dendritic cell surface receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR specifically recognize high mannose N-linked carbohydrates on viral pathogens. Previous studies have shown that these receptors bind the outer trimannose branch Manα1-3[Manα1-6]Manα present in high mannose structures. Although the trimannoside binds to DC-SIGN or DC-SIGNR more strongly than mannose, additional affinity enhancements are observed in the presence of one or more Manα1-2Manα moieties on the nonreducing termini of oligomannose structures. The molecular basis of this enhancement has been investigated by determining crystal structures of DC-SIGN bound to a synthetic six-mannose fragment of a high mannose N-linked oligosaccharide, Manα1-2Manα1-3[Manα1-2Manα1-6]Manα1-6Man and to the disaccharide Manα1-2Man. The structures reveal mixtures of two binding modes in each case. Each mode features typical C-type lectin binding at the principal Ca2+-binding site by one mannose residue. In addition, other sugar residues form contacts unique to each binding mode. These results suggest that the affinity enhancement displayed toward oligosaccharides decorated with the Manα1-2Manα structure is due in part to multiple binding modes at the primary Ca2+ site, which provide both additional contacts and a statistical (entropic) enhancement of binding. The dendritic cell receptor DC-SIGN functions in the initial recognition of pathogens and also in adhesive interactions with T cells that scan the surface of dendritic cells for complementary peptide antigen-major histocompatibility complexes (1Cambi A.C. Figdor C.G. Curr. Opin. Cell Biol. 2003; 15: 539-546Crossref PubMed Scopus (219) Google Scholar, 2Steinman R.M. Cell. 2000; 100: 491-494Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Although the epitope for T cell interactions has not been defined, interactions with pathogens exploit the ability of DC-SIGN to recognize both branched fucosylated structures bearing terminal galactose residues and high mannose N-linked oligosaccharides (3Appelmelk B.J. van Die I. van Vliet S.J. Vandenbroucke-Grauls C.M.J.E. Geijtenbeek T.B.H. van Kooyk Y. J. Immunol. 2003; 170: 1635-1639Crossref PubMed Scopus (382) Google Scholar, 4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar, 5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar). The latter specificity allows DC-SIGN to act as a receptor for several enveloped viruses that bear high mannose structures on their surface glycoproteins, most notably human immunodeficiency virus (HIV) 2The abbreviations used are: HIV, human immunodeficiency virus; CRD, carbohydrate-recognition domain; Man2, Manα1-2Man; Man6b, Manα1-2Manα1-3[Manα1-2Manα1-6]Manα1-6Man; Man3GlcNAc2, GlcNAcβ1-2Manα1-3[GlcNAcβ1-2Manα1-6]Man; Man4, Manα1-3[Manα1-6]Manα1-6Man. (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 7van Kooyk Y. Geijtenbeek T.B.H. Nat. Rev. Immunol. 2003; 3: 697-709Crossref PubMed Scopus (775) Google Scholar, 8van Kooyk Y. Appelmelk B. Geijtenbeek T.B.H. Trends Mol. Med. 2003; 9: 153-159Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). A related receptor found on endothelia in the liver, lymph nodes, and placenta, designated DC-SIGNR or L-SIGN, does not recognize fucosylated carbohydrates but shares with DC-SIGN the ability to bind tightly to high mannose N-linked carbohydrates and to serve as a viral receptor (5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar, 6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, 9Alvarez C.P. Lasala F. Carrillo J. Muñiz O. Corbí A.L. Delgado R. J. Virol. 2002; 76: 6841-6844Crossref PubMed Scopus (541) Google Scholar, 10Pöhlmann S. Baribaud F. Doms R.W. Trends Immunol. 2001; 22: 643-646Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 11Simmons G. Reeves J.D. Grogan C.C. Vandenberghe L.H. Baribaud F. Whitbeck J.C. Burke E. Burchmeier M.J. Soilleux E. Riley J.L. Doms R.W. Bates P. Pohlmann S. Virology. 2003; 305: 115-123Crossref PubMed Scopus (313) Google Scholar). DC-SIGN and DC-SIGNR are members of the C-type lectin family of Ca2+-dependent carbohydrate-binding proteins. The two receptors have similar primary structures, each of which comprises a short N-terminal cytoplasmic tail, a transmembrane anchor, a tetramerization domain, and a C-terminal carbohydrate-recognition domain (CRD) (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). Crystal structures of the DC-SIGN and DC-SIGNR CRDs reveal the typical long form C-type lectin fold (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar). There are three Ca2+ seen in these structures, of which one, designated the principal Ca2+, is common to all C-type lectins. The hallmark of sugar binding to C-type lectins is the direct coordination of the principal Ca2+ by vicinal hydroxyl groups of a pyranose ring, which also form hydrogen bonds with the amino acid side chains that serve as the other Ca2+ ligands (12Drickamer K. Curr. Opin. Struct. Biol. 1999; 9: 585-590Crossref PubMed Scopus (532) Google Scholar). In the case of mannose-like ligands, vicinal, equatorial 3- and 4-OH groups form these coordination and hydrogen bonds. Specificity for particular oligosaccharides comes from additional contacts made to flanking regions of the C-type CRD. Competition assays in which a test ligand is used to compete radiolabeled mannose-bovine serum albumin from immobilized CRD have been used to examine the relative affinities of mannose-containing structures for DC-SIGN and DC-SIGNR (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar, 6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). The trimannose core structure Manα1-3[Manα1-6]Man was found to bind 4-fold better than mannose to DC-SIGN and 2-fold better to DC-SIGNR, and the disaccharide Manα1-2Man shows similar preferences (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar). A pentasaccharide corresponding to the inner five mannoses of a high mannose oligosaccharide but lacking all terminal α1-2-linked mannoses binds 7- and 4-fold better than mannose to DC-SIGN and DC-SIGNR. The full N-linked high mannose oligosaccharide Man9GlcNAc2, however, shows much more substantial affinity enhancements (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar). These data suggested that the presence of the Manα1-2Man moieties at the nonreducing termini of high mannose oligosaccharides might provide substantial affinity enhancements, perhaps by interacting with a secondary binding site for this group. The surface glycoproteins of HIV and other enveloped viruses are relatively rich in Man8 and Man9 structures (13Scanlan C.N. Pantophlet R. Wormald M.R. Saphire E.O. Stanfield R. Wilson I.A. Katinger H. Dwek R.A. Rudd P.M. Burton D.R. J. Virol. 2002; 76: 7306-7321Crossref PubMed Scopus (622) Google Scholar), so high affinity binding to such glycans contributes to selective interaction of DC-SIGN and DC-SIGNR with these pathogens. Here, the mechanism by which terminal Manα1-2Man groups enhance affinity toward DC-SIGN and DC-SIGNR is investigated using synthetic fragments of the full N-linked high mannose structure in binding and structural studies. The data indicate that multiple modes of binding at the DC-SIGN carbohydrate-binding site provide a statistical enhancement of the affinity but do not account for all of the observed affinity differences. The different binding orientations feature contacts between the terminal mannose and different regions of the proteins, which likely provide the remaining component of the increased affinity for larger glycans. Protein Expression—The DC-SIGN carbohydrate-recognition domain was expressed in Escherichia coli as described (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar) and used for cocrystallization with Manα1-2Man. A similar construct lacking the C-terminal 12 residue extension was used for cocrystallization with Man6. Both proteins were purified as described (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). Synthesis and Purification of Man6 and Man9 Oligosaccharides—Compounds Man9 and Man6a (Fig. 1) were prepared analogously to those previously described in the literature (14Ratner D.M. Adams E.W. Su J. O'Keefe B.R. Mrksich M. Seeberger P.H. Chembiochem. 2004; 5: 379-382Crossref PubMed Scopus (179) Google Scholar, 15Ratner D.M. Plante O.J. Seeberger P.H. Eur. J. Org. Chem. 2002; 2002: 826-833Crossref Scopus (81) Google Scholar). O-Me protection at the reducing end was chosen to diminish the possible interference of the linker with the binding site of the protein. Compound Man6b was prepared following the same approach as Man9, using methyl 2,3,4-tri-O-benzyl-α-d-mannopyranoside (16Ding X. Wang W. Kong F. Carbohydr. Res. 1997; 303: 445-448Crossref Scopus (47) Google Scholar, 17Sondheimer S.J. Eby R. Schuerch C. Carbohydr. Res. 1978; 60: 187-192Crossref Scopus (43) Google Scholar) as the core sugar unit. After removal of all protecting groups, the compounds were dialyzed two times each for 12 h against 2 liters of Millipore water and The Manα1-2Man disaccharide was from binding assays were using expressed CRDs of DC-SIGN and DC-SIGNR, with serum albumin as the ligand (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar). The assays were at in that the was in were were using the Scopus Google Scholar). and of DC-SIGN CRD with or Man6b (Fig. 1) were at by of to of in a for and for The that for the and The that for the and The for both The were to a of with in and at data data were on at of the data were on at of the data were with and Biol. PubMed Scopus Google Scholar) for DC-SIGN CRD ligand cell observed and from multiple test ligand and and observed structure and structure for the and test and observed structure and structure for the and test in most observed and from multiple and observed structure and structure for the and test in a of both the Man6b and complexes were to the previously DC-SIGN (5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar), the latter was using different The one of the than to direct the two structures were by molecular with the DC-SIGN CRD from the The structure was with the Biol. PubMed Scopus Google Scholar), which a of and the of for data to The Man6b was with the Scopus Google Scholar), which a of and the of for data to and for both structures were with Adams P. R.W. J. M. Biol. PubMed Scopus Google Scholar). The was with and the that the ligand is bound to the site in two orientations in both structures. The two were of and on the of the and each ligand 2 shows the from the but the were to of in that were hydrogen to or other water The of the DC-SIGN residues of two of the Ca2+, and water The of the DC-SIGN residues of two of the Ca2+, and water The are in of for DC-SIGN and examine the of the Manα1-2Man groups present on the termini of high mannose oligosaccharide to DC-SIGN and DC-SIGNR three synthetic oligomannose structures corresponding to fragments of were in the Man9 is the full structure that to in high mannose N-linked carbohydrates (Fig. Man6a the three terminal mannoses of Man9 (Fig. Man6b is the of Man9 that the branch (Fig. These compounds were relative to mannose, and the full structure purified from was also for direct The two Man6 structures bind with a affinity enhancement relative to mannose, the Man9 binds as strongly as the Man6 glycans. The full shows binding than Man9 data for ligand binding to DC-SIGN and DC-SIGNR of mannose for from that the of in those with the shown in the of the the assays were with a different of serum of mannose for from that the of in those with the shown in the of the the assays were with a different of serum of mannose for from that the of in those with the shown in the of the the assays were with a different of serum of mannose for from that the of in those with the shown in the of the the assays were with a different of serum in a of Man6b to of complexes between Man9, and Man6b with the DC-SIGN CRD with the The structure of this was at The structure is to that previously described for complexes with (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar) and (5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar). The ligand is bound in two in a at designated the (Fig. A and and designated the (Fig. and the mannoses in the three are in the and two in the The mannose that one of the outer branched trimannose binds to the primary Ca2+ site and was observed to bind to the Ca2+ in both the (5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar) and (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar) structures. The to the seen in these crystal structures (Fig. The branch of the oligosaccharide is not however, which is the and hydrogen bonds between the mannose and and other residues in DC-SIGN that were observed in the structures (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar, 5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar). The for this is the that the crystal is to the (5Guo Y. Feinberg H. Conroy E. Mitchell D.A. Alvarez R. Taylor M.E. Weis W.I. Drickamer K. Nat. Struct. Mol. Biol. 2004; 11: 591-598Crossref PubMed Scopus (487) Google Scholar). In the and structures, the mannose has than the mannose, that more The α1-2-linked mannose at the nonreducing contacts In the the same mannose residue is bound to the Ca2+, but is by a a the pyranose the the of the 3- and 4-OH groups so that form the Ca2+ coordination and hydrogen bonds of C-type interactions (Fig. and A similar was observed in complexes of proteins with ligands S. Feinberg H. D.A. Drickamer K. Weis W.I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In this two are the mannose at the Ca2+ site and the nonreducing terminal α1-2-linked mannose, which hydrogen bonds with and and which also with the of the (Fig. that the side has in the recognition of ligand in Manα1-2Man is is not possible to these residues to the or of Man6b or a of both (Fig. of the and orientations is shown in of Manα1-2Man to DC-SIGN might have additional for the Manα1-2Man residues found at the nonreducing termini of high mannose the CRD was with Manα1-2Man. The structure of the disaccharide binding in the principal Ca2+ other were observed at Manα1-2Man binds at the principal Ca2+ site in two related by a the The is to that of the Manα1-2Man in the Man6b ligand and the same contacts with the with (Fig. A and In the a sugar is and the typical Ca2+ coordination and hydrogen bonds (Fig. and mannose is to the mannose in the Man6 The however, do not the sugar bound at the Ca2+ is the reducing or nonreducing end of the is possible that is a of the In the Man6b the nonreducing α1-2-linked mannose is not The for this sugar is not in the Man6b so the of for this residue in the due to is also possible that the interaction with seen in the Man6b structure does not for the of to form this in the of Man9 the two modes of binding observed in the Man6b and structures are to a oligosaccharide, for by of the Wormald M.R. Dwek R.A. Eur. J. PubMed Scopus Google Scholar) were on the two orientations of previously (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar), of the outer branched trimannose between the of the oligosaccharide and the (Fig. A and with the side of to of the which the terminal α1-2-linked mannose of the outer also with the with the possible of interference between and the residue (Fig. in which the terminal Manα1-2Man groups of the other were shows (Fig. and results were with of from the with a D.A. C.N. S. Y. R. P. Wormald M.R. Stanfield Rudd P.M. Dwek R.A. Katinger H. Burton D.R. Wilson I.A. Science. 2003; PubMed Scopus Google Scholar), in this case to the were the outer branched mannose were not The structure of the two binding modes for the The binding mode to that observed in crystal structures, a site for the outer branched trimannose of high mannose N-linked In this additional contacts are between a nonreducing α1-2-linked terminal mannose and of DC-SIGN is also in binding to fucosylated and a terminal in the (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar). The latter binds more strongly to DC-SIGN relative to mannose and 4-fold more than the trimannose that the additional interactions to a binding was observed in which the mannose at the principal Ca2+ site is interactions between the nonreducing terminal mannose and the that this to bind to the as part of a full structure (Fig. The of the binding modes of the Man6b was by the structure of the Manα1-2Man which shows the same In this the binding mode the nonreducing end the a different of the and Man6 but in case is that this binding mode The that other binding for this ligand were observed that are other secondary that with terminal Manα1-2Man in larger N-linked high mannose oligosaccharides that might account for binding to such glycans. The of binding each in unique contacts with a of the affinity enhancements observed high mannose structures are decorated with α1-2-linked mannose residues at the nonreducing and to the of and and for the of the with the affinity is related to the affinity of the binding modes by the the this as and that for two binding modes of and so the ability to bind in two modes additional of corresponding to at binding modes the observed times the additional binding modes the by than a of The of this statistical by the binding of Manα1-2Man with the of 3- and 4-OH groups, mannose bind in of two orientations related by a that the 3- and 4-OH groups, as described In the each residue in bind in a of binding all of these modes were the relative for the disaccharide that of the possible of binding the and groups, which has been observed in the case of galactose binding to C-type lectins Drickamer K. Weis W.I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The is seen for DC-SIGNR, but the is for which that are interactions with DC-SIGN made by the sugar of the is also possible that mannose bind in one of two as seen in crystal structures of proteins bound to which a than a in the binding site S. Feinberg H. D.A. Drickamer K. Weis W.I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Drickamer K. Weis W.I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). more ligands, the binding mode observed in and as a relatively high affinity mode. The core of the full Man9 which all Manα1-2Man groups, binds to DC-SIGN better than mannose and 4-fold better in the case of DC-SIGNR. also the inner branched trimannose in the core that in the of the (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar) might also The ability to bind to the inner or outer branched trimannose likely the enhancement of (4Feinberg H. Mitchell D.A. Drickamer K. Weis W.I. Science. 2001; 294: 2163-2166Crossref PubMed Scopus (577) Google Scholar). Man6b binds better than mannose to DC-SIGN and better than mannose to DC-SIGNR Man6b the inner but the outer branched trimannose binding mode and the mode in which the nonreducing terminal is bound are The and 4-fold enhancement of Man6b binding to DC-SIGN and DC-SIGNR, for in part by the binding mode. In the the α1-2-linked terminal mannose on Man6b additional interactions relative to which might this In the Manα1-2Man present on the termini of both the and of Man6b bind in this but in the structure three modes at the principal Ca2+ site the outer branched trimannose the two termini of the two are the of the two orientations observed in the Man6b is likely that interaction of the trimannose binding mode and the statistical of the mode both to the observed affinity the is of affinity than the nonreducing Manα1-2Man binding the affinity enhancements by the latter than a of that the observed the relative affinities of the two binding with the of in both the Man6 and structures, so the between these that the observed mode has of the two different the are and the is that in by in contacts with by to binding orientations and likely all possible modes are not the binding site vicinal, equatorial groups for Ca2+ The affinities of Man6a for DC-SIGN and DC-SIGNR are to a similar as for In this the outer branched trimannose is but Manα1-2Man moieties are to these two Manα1-2Man groups present on the of the inner branched trimannose provide two more binding is also possible that the inner branched trimannose this to have a similar and of binding modes as Man6b, their different structures. In the full Man9 the inner and outer branched trimannose are as as the Manα1-2Man groups to the that the on the branch of the inner trimannose structure provide two more have a of which enhancement relative to Man6. Although this several which modes of binding might or might not is that the ability of high mannose oligosaccharides to with DC-SIGN and DC-SIGNR in multiple orientations to statistical affinity enhancements that are with the the different binding modes also in determining the affinity of each the in affinity displayed by the full structure Man9 is to the inner residues the of sugar groups such that is a for or contacts are between these residues and the surface of the protein. DC-SIGN and DC-SIGNR serve as receptors for HIV and several other enveloped viruses by binding to the high mannose oligosaccharides present on viral surface The CRD of DC-SIGN specifically of the the outer branched unique to these The presence of Manα1-2Man the affinity of oligomannose toward these by this disaccharide binds more strongly than The CRD has high affinity for oligomannose structures, and tetramerization likely enhancements for of such structures (6Mitchell D.A. Fadden A.J. Drickamer K. J. Biol. Chem. 2001; 276: 28939-28945Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar, H. Y. Mitchell D.A. Drickamer K. Weis W.I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The ability of DC-SIGN and DC-SIGNR to bind high mannose glycans in multiple orientations this binding of of CRDs to glycans displayed in on the surface of the as previously for cell surface recognition by proteins S. Feinberg H. D.A. Drickamer K. Weis W.I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). There are with the mechanism by which a to HIV, binds specifically to the terminal Manα1-2Man groups present on high mannose carbohydrates (13Scanlan C.N. Pantophlet R. Wormald M.R. Saphire E.O. Stanfield R. Wilson I.A. Katinger H. Dwek R.A. Rudd P.M. Burton D.R. J. Virol. 2002; 76: 7306-7321Crossref PubMed Scopus (622) Google Scholar, R.W. M. R. Katinger H. J. Virol. 2002; 76: PubMed Scopus Google Scholar). The binding site of to recognize specifically a of Manα1-2Man present on the nonreducing termini of Man9, but at two of the three branch termini bind to this which statistical enhancement of is in this case by the which is to binding that the of these structures on the viral surface D.A. C.N. S. Y. R. P. Wormald M.R. Stanfield Rudd P.M. Dwek R.A. Katinger H. Burton D.R. Wilson I.A. Science. 2003; PubMed Scopus Google Scholar, D.A. Stanfield Katinger H. Burton D.R. Wilson I.A. S. PubMed Scopus Google Scholar). for and and for of the glycans from