8b2i: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[8b2i]] is a 2 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=8B2I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B2I FirstGlance]. <br>
<table><tr><td colspan='2'>[[8b2i]] is a 2 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=8B2I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B2I FirstGlance]. <br>
</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=OQ9:4-methanoyl-~{N}-methyl-~{N}-(2-sulfanylethyl)benzamide'>OQ9</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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]] 1.4&#8491;</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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene>, <scene name='pdbligand=OQ9:4-methanoyl-~{N}-methyl-~{N}-(2-sulfanylethyl)benzamide'>OQ9</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></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=8b2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b2i OCA], [https://pdbe.org/8b2i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b2i RCSB], [https://www.ebi.ac.uk/pdbsum/8b2i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b2i 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=8b2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b2i OCA], [https://pdbe.org/8b2i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b2i RCSB], [https://www.ebi.ac.uk/pdbsum/8b2i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b2i ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Molecules that stabilize protein-protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points for PPI stabilizing matter is highly challenging, and chemical optimization is labor-intensive. Inspired by chemical crosslinking and reversible covalent fragment-based drug discovery, we developed an approach that we term "molecular locks" to rapidly access molecular glue-like tool compounds. These dual-covalent small molecules reversibly react with a nucleophilic amino acid on each of the partner proteins to dynamically crosslink the protein complex. The PPI between the hub protein 14-3-3 and estrogen-related receptor gamma (ERRgamma) was used as a pharmacologically relevant case study. Based on a focused library of dual-reactive small molecules, a molecular glue tool compound was rapidly developed. Biochemical assays and X-ray crystallographic studies validated the ternary covalent complex formation and overall PPI stabilization via dynamic covalent crosslinking. The molecular lock approach is highly selective for the specific 14-3-3/ERRgamma complex, over other 14-3-3 complexes. This selectivity is driven by the interplay of molecular reactivity and molecular recognition of the composite PPI binding interface. The long lifetime of the dual-covalent locks enabled the selective stabilization of the 14-3-3/ERRgamma complex even in the presence of several other competing 14-3-3 clients with higher intrinsic binding affinities. The molecular lock approach enables systematic, selective, and potent stabilization of protein complexes to support molecular glue drug discovery.
Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRgamma Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.,Somsen BA, Schellekens RJC, Verhoef CJA, Arkin MR, Ottmann C, Cossar PJ, Brunsveld L J Am Chem Soc. 2023 Mar 16. doi: 10.1021/jacs.2c12781. PMID:36926879<ref>PMID:36926879</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8b2i" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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__TOC__
</StructureSection>
</StructureSection>

Revision as of 08:15, 7 February 2024

Ternary structure of 14-3-3s, ERRg phosphopeptide and dual-reactive compound 4

8b2i, resolution 1.40Å

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