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6mxr
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the dimeric bH1-Fab variant [HC-Y33W,HC-D98M,HC-G99M]== | |
| + | <StructureSection load='6mxr' size='340' side='right'caption='[[6mxr]], [[Resolution|resolution]] 2.04Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6mxr]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MXR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MXR FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6mxs|6mxs]], [[6my4|6my4]], [[6my5|6my5]]</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=6mxr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mxr OCA], [http://pdbe.org/6mxr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6mxr RCSB], [http://www.ebi.ac.uk/pdbsum/6mxr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6mxr ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Solution stability is an important factor in the optimization of engineered biotherapeutic candidates such as monoclonal antibodies because of its possible effects on manufacturability, pharmacology, efficacy and safety. A detailed atomic understanding of the mechanisms governing self-association of natively folded protein monomers is required to devise predictive tools to guide screening and re-engineering along the drug development pipeline. We investigated pairs of affinity-matured full-size antibodies and observed drastically different propensities to aggregate from variants differing by a single amino-acid. Biophysical testing showed that antigen-binding fragments (Fabs) from the aggregating antibodies also reversibly associated with equilibrium dissociation constants in the low-micromolar range. Crystal structures (PDB accession codes 6MXR, 6MXS, 6MY4, 6MY5) and bottom-up hydrogen-exchange mass spectrometry revealed that Fab self-association occurs in a symmetric mode that involves the antigen complementarity-determining regions. Subtle local conformational changes incurred upon point mutation of monomeric variants foster formation of complementary polar interactions and hydrophobic contacts to generate a dimeric Fab interface. Testing of popular in silico tools generally indicated low reliabilities for predicting the aggregation propensities observed. A structure-aggregation data set is provided here in order to stimulate further improvements of in silico tools for prediction of native aggregation. Incorporation of intermolecular docking, conformational flexibility, and short-range packing interactions may all be necessary features of the ideal algorithm. | ||
| - | + | Binding symmetry and surface flexibility mediate antibody self-association.,Schrag JD, Picard ME, Gaudreault F, Gagnon LP, Baardsnes J, Manenda MS, Sheff J, Deprez C, Baptista C, Hogues H, Kelly JF, Purisima EO, Shi R, Sulea T MAbs. 2019 Jul 18:1-19. doi: 10.1080/19420862.2019.1632114. PMID:31318308<ref>PMID:31318308</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6mxr" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Shi, R]] | ||
| + | [[Category: Aggregation]] | ||
| + | [[Category: Antibody self-assembly]] | ||
| + | [[Category: Fab fragment]] | ||
| + | [[Category: Immune system]] | ||
Revision as of 06:21, 31 July 2019
Crystal structure of the dimeric bH1-Fab variant [HC-Y33W,HC-D98M,HC-G99M]
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