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5xjf

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Revision as of 06:52, 14 October 2020

Crystal structure of fucosylated IgG Fc Y296W mutant complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa

Structural highlights

5xjf is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , ,
Related:	5xje
Gene:	FCGR3A, CD16A, FCG3, FCGR3, IGFR3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FCG3A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.^[1] ^[2] ^[3] ^[4]

Function

[IGG1_HUMAN] Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:22158414, PubMed:20176268). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:20176268, PubMed:17576170).^[5] ^[6] ^[7] [FCG3A_HUMAN] Receptor for the Fc region of IgG. Binds complexed or aggregated IgG and also monomeric IgG. Mediates antibody-dependent cellular cytotoxicity (ADCC) and other antibody-dependent responses, such as phagocytosis.^[8] ^[9]

Publication Abstract from PubMed

Antibody-dependent cellular cytotoxicity (ADCC) is promoted through interaction between the Fc region of immunoglobulin G1 (IgG1) and Fcgamma receptor IIIa (FcgammaRIIIa), depending on N-glycosylation of these glycoproteins. In particular, core fucosylation of IgG1-Fc N-glycans negatively affects this interaction and thereby compromises ADCC activity. To address the mechanisms of this effect, we performed replica-exchange molecular dynamics simulations based on crystallographic analysis of a soluble form of FcgammaRIIIa (sFcgammaRIIIa) in complex with IgG1-Fc. Our simulation highlights increased conformational fluctuation of the N-glycan at Asn162 of sFcgammaRIIIa upon fucosylation of IgG1-Fc, consistent with crystallographic data giving no interpretable electron density for this N-glycan, except for the innermost part. The fucose residue disrupts optimum intermolecular carbohydrate-carbohydrate interactions, rendering this sFcgammaRIIIa glycan distal from the Fc glycan. Moreover, our simulation demonstrates that core fucosylation of IgG1-Fc affects conformational dynamics and rearrangements of surrounding amino acid residues, typified by Tyr296 of IgG1-Fc, which was more extensively involved in the interaction with sFcgammaRIIIa without Fc core fucosylation. Our findings offer a structural foundation for designing and developing therapeutic antibodies with improved ADCC activity.

Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcgamma receptor IIIa.,Sakae Y, Satoh T, Yagi H, Yanaka S, Yamaguchi T, Isoda Y, Iida S, Okamoto Y, Kato K Sci Rep. 2017 Oct 23;7(1):13780. doi: 10.1038/s41598-017-13845-8. PMID:29062024^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Grier JT, Forbes LR, Monaco-Shawver L, Oshinsky J, Atkinson TP, Moody C, Pandey R, Campbell KS, Orange JS. Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity. J Clin Invest. 2012 Oct 1;122(10):3769-80. doi: 10.1172/JCI64837. Epub 2012 Sep, 24. PMID:23006327 doi:http://dx.doi.org/10.1172/JCI64837
↑ Jawahar S, Moody C, Chan M, Finberg R, Geha R, Chatila T. Natural Killer (NK) cell deficiency associated with an epitope-deficient Fc receptor type IIIA (CD16-II). Clin Exp Immunol. 1996 Mar;103(3):408-13. PMID:8608639
↑ de Haas M, Koene HR, Kleijer M, de Vries E, Simsek S, van Tol MJ, Roos D, von dem Borne AE. A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa. J Immunol. 1996 Apr 15;156(8):2948-55. PMID:8609432
↑ de Vries E, Koene HR, Vossen JM, Gratama JW, von dem Borne AE, Waaijer JL, Haraldsson A, de Haas M, van Tol MJ. Identification of an unusual Fc gamma receptor IIIa (CD16) on natural killer cells in a patient with recurrent infections. Blood. 1996 Oct 15;88(8):3022-7. PMID:8874200
↑ Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20. PMID:17576170 doi:http://dx.doi.org/10.1146/annurev.genet.41.110306.130340
↑ Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S41-52. doi:, 10.1016/j.jaci.2009.09.046. PMID:20176268 doi:http://dx.doi.org/10.1016/j.jaci.2009.09.046
↑ McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128. PMID:22158414 doi:http://dx.doi.org/10.1038/nri3128
↑ Ferrara C, Grau S, Jager C, Sondermann P, Brunker P, Waldhauer I, Hennig M, Ruf A, Rufer AC, Stihle M, Umana P, Benz J. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between Fc{gamma}RIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A. 2011 Jul 18. PMID:21768335 doi:10.1073/pnas.1108455108
↑ Mizushima T, Yagi H, Takemoto E, Shibata-Koyama M, Isoda Y, Iida S, Masuda K, Satoh M, Kato K. Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells. 2011 Nov;16(11):1071-1080. doi:, 10.1111/j.1365-2443.2011.01552.x. PMID:22023369 doi:10.1111/j.1365-2443.2011.01552.x
↑ Sakae Y, Satoh T, Yagi H, Yanaka S, Yamaguchi T, Isoda Y, Iida S, Okamoto Y, Kato K. Conformational effects of N-glycan core fucosylation of immunoglobulin G Fc region on its interaction with Fcgamma receptor IIIa. Sci Rep. 2017 Oct 23;7(1):13780. doi: 10.1038/s41598-017-13845-8. PMID:29062024 doi:http://dx.doi.org/10.1038/s41598-017-13845-8

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5xjf"

@@ Line 1: / Line 1: @@
 ==Crystal structure of fucosylated IgG Fc Y296W mutant complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa==
-<StructureSection load='5xjf' size='340' side='right' caption='[[5xjf]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+<StructureSection load='5xjf' size='340' side='right'caption='[[5xjf]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5xjf]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XJF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XJF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5xjf]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XJF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5XJF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5xje|5xje]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xjf OCA], [http://pdbe.org/5xjf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xjf RCSB], [http://www.ebi.ac.uk/pdbsum/5xjf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xjf ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FCGR3A, CD16A, FCG3, FCGR3, IGFR3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5xjf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xjf OCA], [http://pdbe.org/5xjf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xjf RCSB], [http://www.ebi.ac.uk/pdbsum/5xjf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xjf ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 25: / Line 26: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Iida, S]]
 [[Category: Isoda, Y]]

5xjf

From Proteopedia

Revision as of 06:52, 14 October 2020

Crystal structure of fucosylated IgG Fc Y296W mutant complexed with bis-glycosylated soluble form of Fc gamma receptor IIIa

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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