6my4: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6my4 is ~~ON HOLD until Nov 01 2020~~

==Crystal structure of the dimeric bH1-Fab variant [HC-Y33W,HC-D98M,HC-G99M,LC-S30bR]==

== Structural highlights ==

<table><tr><td colspan='2'>[[6my4]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MY4 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>

<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6mxs|6mxs]], [[6mxr|6mxr]], [[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=6my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6my4 OCA], [http://pdbe.org/6my4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6my4 RCSB], [http://www.ebi.ac.uk/pdbsum/6my4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6my4 ProSAT]</span></td></tr>

</table>

== 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.

~~Authors~~:

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>

~~Description~~:

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

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Large Structures]]

[[Category: Manenda, M]]

[[Category: Picard, M E]]

[[Category: Shi, R]]

[[Category: Antibody assembly]]

[[Category: Dimeric fab]]

[[Category: Fab fragment]]

[[Category: Immune system]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6my4 is ON HOLD  until Nov 01 2020
+==Crystal structure of the dimeric bH1-Fab variant [HC-Y33W,HC-D98M,HC-G99M,LC-S30bR]==
+<StructureSection load='6my4' size='340' side='right'caption='[[6my4]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6my4]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MY4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MY4 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6mxs|6mxs]], [[6mxr|6mxr]], [[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=6my4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6my4 OCA], [http://pdbe.org/6my4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6my4 RCSB], [http://www.ebi.ac.uk/pdbsum/6my4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6my4 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.
-Authors:
+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>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6my4" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Manenda, M]]
+[[Category: Picard, M E]]
+[[Category: Shi, R]]
+[[Category: Antibody assembly]]
+[[Category: Dimeric fab]]
+[[Category: Fab fragment]]
+[[Category: Immune system]]