3wn5

From Proteopedia

(Difference between revisions)

Revision as of 17:39, 11 August 2016

Crystal structure of asymmetrically engineered Fc variant in complex with FcgRIIIa

Structural highlights

3wn5 is a 6 chain structure. 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. [FCG3A_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.^[1] ^[2] ^[3] ^[4]

Function

[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.^[5] ^[6]

Publication Abstract from PubMed

Enhancing the effector function by optimizing the interaction between Fc and Fcgamma receptor (FcgammaR) is a promising approach to enhance the potency of anticancer monoclonal antibodies (mAbs). To date, a variety of Fc engineering approaches to modulate the interaction have been reported, such as afucosylation in the heavy chain Fc region or symmetrically introducing amino acid substitutions into the region, and there is still room to improve FcgammaR binding and thermal stability of the CH2 domain with these approaches. Recently, we have reported that asymmetric Fc engineering, which introduces different substitutions into each Fc region of heavy chain, can further improve the FcgammaR binding while maintaining the thermal stability of the CH2 domain by fine-tuning the asymmetric interface between the Fc domain and FcgammaR. However, the structural mechanism by which the asymmetrically engineered Fc improved FcgammaR binding remained unclear. In order to elucidate the mechanism, we solved the crystal structure of a novel asymmetrically engineered Fc, asym-mAb23, in complex with FcgammaRIIIa. Asym-mAb23 has enhanced binding affinity for both FcgammaRIIIa and FcgammaRIIa at the highest level of previously reported Fc variants. The structural analysis reveals the features of the asymmetrically engineered Fc in comparison with symmetric Fc and how each asymmetrically introduced substitution contributes to the improved interaction between asym-mAb23 and FcgammaRIIIa. This crystal structure could be utilized to enable us to design a more potent asymmetric Fc.

Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for FcgammaRs.,Mimoto F, Kadono S, Katada H, Igawa T, Kamikawa T, Hattori K Mol Immunol. 2014 Mar;58(1):132-8. doi: 10.1016/j.molimm.2013.11.017. Epub 2013, Dec 14. PMID:24334029^[7]

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
↑ 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
↑ Mimoto F, Kadono S, Katada H, Igawa T, Kamikawa T, Hattori K. Crystal structure of a novel asymmetrically engineered Fc variant with improved affinity for FcgammaRs. Mol Immunol. 2014 Mar;58(1):132-8. doi: 10.1016/j.molimm.2013.11.017. Epub 2013, Dec 14. PMID:24334029 doi:http://dx.doi.org/10.1016/j.molimm.2013.11.017

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/3wn5"

@@ Line 1: / Line 1: @@
 ==Crystal structure of asymmetrically engineered Fc variant in complex with FcgRIIIa==
 <StructureSection load='3wn5' size='340' side='right' caption='[[3wn5]], [[Resolution|resolution]] 2.78&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[3wn5]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WN5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WN5 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=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=FUL:BETA-L-FUCOSE'>FUL</scene>, <scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</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=3wn5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wn5 RCSB], [http://www.ebi.ac.uk/pdbsum/3wn5 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=3wn5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wn5 OCA], [http://pdbe.org/3wn5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wn5 RCSB], [http://www.ebi.ac.uk/pdbsum/3wn5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wn5 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3wn5" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

3wn5

From Proteopedia

Revision as of 17:39, 11 August 2016

Crystal structure of asymmetrically engineered Fc variant in complex with FcgRIIIa

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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