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| | <StructureSection load='6mxr' size='340' side='right'caption='[[6mxr]], [[Resolution|resolution]] 2.04Å' scene=''> | | <StructureSection load='6mxr' size='340' side='right'caption='[[6mxr]], [[Resolution|resolution]] 2.04Å' scene=''> |
| | == Structural highlights == | | == 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> | + | <table><tr><td colspan='2'>[[6mxr]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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 [https://proteopedia.org/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> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.04Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='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> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mxr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mxr OCA], [https://pdbe.org/6mxr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mxr RCSB], [https://www.ebi.ac.uk/pdbsum/6mxr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mxr ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/V9HW68_HUMAN V9HW68_HUMAN] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Shi, R]] | + | [[Category: Shi R]] |
| - | [[Category: Aggregation]]
| + | |
| - | [[Category: Antibody self-assembly]]
| + | |
| - | [[Category: Fab fragment]]
| + | |
| - | [[Category: Immune system]]
| + | |
| Structural highlights
Function
V9HW68_HUMAN
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[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. Binding symmetry and surface flexibility mediate antibody self-association. MAbs. 2019 Jul 18:1-19. doi: 10.1080/19420862.2019.1632114. PMID:31318308 doi:http://dx.doi.org/10.1080/19420862.2019.1632114
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