View source for 6ywz


==Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid==
<StructureSection load='6ywz' size='340' side='right'caption='[[6ywz]], [[Resolution|resolution]] 2.12&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ywz]] 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=6YWZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YWZ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.12&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARG:ARGININE'>ARG</scene>, <scene name='pdbligand=LEU:LEUCINE'>LEU</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PWN:2-[(~{E})-(4-oxidanylidenebutanoylhydrazinylidene)methyl]benzoic+acid'>PWN</scene>, <scene name='pdbligand=THR:THREONINE'>THR</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=6ywz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ywz OCA], [https://pdbe.org/6ywz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ywz RCSB], [https://www.ebi.ac.uk/pdbsum/6ywz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ywz ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SHAN1_HUMAN SHAN1_HUMAN] Seems to be an adapter protein in the postsynaptic density (PSD) of excitatory synapses that interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and Homer, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
beta-Strand mediated protein-protein interactions (PPIs) represent underexploited targets for chemical probe development despite representing a significant proportion of known and therapeutically relevant PPI targets. beta-Strand mimicry is challenging given that both amino acid side-chains and backbone hydrogen-bonds are typically required for molecular recognition, yet these are oriented along perpendicular vectors. This paper describes an alternative approach, using GKAP/SHANK1 PDZ as a model and dynamic ligation screening to identify small-molecule replacements for tranches of peptide sequence. A peptide truncation of GKAP functionalized at the N- and C-termini with acylhydrazone groups was used as an anchor. Reversible acylhydrazone bond exchange with a library of aldehyde fragments in the presence of the protein as template and in situ screening using a fluorescence anisotropy (FA) assay identified peptide hybrid hits with comparable affinity to the GKAP peptide binding sequence. Identified hits were validated using FA, ITC, NMR and X-ray crystallography to confirm selective inhibition of the target PDZ-mediated PPI and mode of binding. These analyses together with molecular dynamics simulations demonstrated the ligands make transient interactions with an unoccupied basic patch through electrostatic interactions, establishing proof-of-concept that this unbiased approach to ligand discovery represents a powerful addition to the armory of tools that can be used to identify PPI modulators.

Identification of beta-strand mediated protein-protein interaction inhibitors using ligand-directed fragment ligation.,Hegedus Z, Hobor F, Shoemark DK, Celis S, Lian LY, Trinh CH, Sessions RB, Edwards TA, Wilson AJ Chem Sci. 2021 Jan 6;12(6):2286-2293. doi: 10.1039/d0sc05694d. PMID:34163995<ref>PMID:34163995</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6ywz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Celis S]]
[[Category: Edwards TA]]
[[Category: Hegedus Z]]
[[Category: Hobor F]]
[[Category: Lian LJ]]
[[Category: Sessions RB]]
[[Category: Shoemark DK]]
[[Category: Trinh CH]]
[[Category: Wilson AJ]]