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4bm7

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Revision as of 13:50, 5 August 2016

Crystal Structure of IgG Fc F241A mutant with native glycosylation

Structural highlights

4bm7 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[IGHG1_HUMAN] Defects in IGHG1 are a cause of multiple myeloma (MM) [MIM:254500]. MM is a malignant tumor of plasma cells usually arising in the bone marrow and characterized by diffuse involvement of the skeletal system, hyperglobulinemia, Bence-Jones proteinuria and anemia. Complications of multiple myeloma are bone pain, hypercalcemia, renal failure and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity and patients have a high prevalence of infection. Amyloidosis may develop in some patients. Multiple myeloma is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Note=A chromosomal aberration involving IGHG1 is found in multiple myeloma. Translocation t(11;14)(q13;q32) with the IgH locus. Translocation t(11;14)(q13;q32) with CCND1; translocation t(4;14)(p16.3;q32.3) with FGFR3; translocation t(6;14)(p25;q32) with IRF4.

Publication Abstract from PubMed

Biologically active conformations of the IgG1 Fc homodimer are maintained by multiple hydrophobic interactions between the protein surface and the N-glycan. The Fc glycan modulates biological effector functions, including antibody-dependent cellular cytotoxicity (ADCC) which is mediated in part through the activatory Fc receptor, FcgammaRIIIA. Consistent with previous reports, we found that site-directed mutations disrupting the protein-carbohydrate interface (F241A, F243A, V262E and V264E) increased galactosylation and sialylation of the Fc and, concomitantly, reduced the affinity for FcgammaRIIIA. We rationalized this effect by crystallographic analysis of the IgG1 Fc F241A mutant, determined here to a resolution of 1.9 A, which revealed localised destabilisation of this glycan-protein interface. Given that sialylation of Fc glycans decreases ADCC, one explanation for the effect of these mutants on FcgammaRIIIA binding is their increased sialylation. However, a glycan-engineered IgG1 with hypergalactosylated and hypersialylated glycans exhibited unchanged binding affinity to FcgammaRIIIA. Moreover, when we expressed these mutants as a chemically uniform (Man5GlcNAc2) glycoform, the individual effect of each mutation on FcgammaRIIIA affinity was preserved. This effect was broadly recapitulated for other Fc receptors (FcgammaRI, FcgammaRIIA, FcgammaRIIB and FcgammaRIIIB). These data indicate that destabilisation of the glycan-protein interactions, rather than increased terminal glycan processing, modifies the Fc conformation(s) relevant for FcgammaR binding. Engineering of the protein-carbohydrate interface thus provides an independent parameter in the engineering of Fc effector functions, and a route to the synthesis of new classes of Fc domain with novel combinations of affinities for activatory and inhibitory Fc receptors.

Engineering hydrophobic protein-carbohydrate interactions to fine-tune monoclonal antibodies.,Yu X, Baruah K, Harvey DJ, Vasiljevic S, Alonzi DS, Song BD, Higgins MK, Bowden TA, Scanlan CN, Crispin M J Am Chem Soc. 2013 Jun 7. PMID:23745692^[1]

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

References

↑ Yu X, Baruah K, Harvey DJ, Vasiljevic S, Alonzi DS, Song BD, Higgins MK, Bowden TA, Scanlan CN, Crispin M. Engineering hydrophobic protein-carbohydrate interactions to fine-tune monoclonal antibodies. J Am Chem Soc. 2013 Jun 7. PMID:23745692 doi:10.1021/ja4014375

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4bm7"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of IgG Fc F241A mutant with native glycosylation==
 <StructureSection load='4bm7' size='340' side='right' caption='[[4bm7]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4bm7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BM7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BM7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4bm7]] is a 2 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=4BM7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BM7 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=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></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=4bm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bm7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bm7 RCSB], [http://www.ebi.ac.uk/pdbsum/4bm7 PDBsum]</span></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=4bm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bm7 OCA], [http://pdbe.org/4bm7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bm7 RCSB], [http://www.ebi.ac.uk/pdbsum/4bm7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bm7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4bm7" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Alonzi, D S]]
 [[Category: Baruah, K]]

4bm7

From Proteopedia

Revision as of 13:50, 5 August 2016

Crystal Structure of IgG Fc F241A mutant with native glycosylation

Structural highlights

Disease

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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