6yx1: Difference between revisions
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==Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid== | ==Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid== | ||
<StructureSection load='6yx1' size='340' side='right'caption='[[6yx1]]' scene=''> | <StructureSection load='6yx1' size='340' side='right'caption='[[6yx1]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YX1 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6yx1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YX1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YX1 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </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=PWT:2-[[2-(5-oxidanylidenepentanoyl)hydrazinyl]methyl]benzoic+acid'>PWT</scene>, <scene name='pdbligand=THR:THREONINE'>THR</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[6ywz|6ywz]], [[6yx0|6yx0]], [[6yx2|6yx2]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SHANK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6yx1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yx1 OCA], [https://pdbe.org/6yx1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yx1 RCSB], [https://www.ebi.ac.uk/pdbsum/6yx1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yx1 ProSAT]</span></td></tr> | |||
</table> | </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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6yx1" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Celis S]] | [[Category: Celis, S]] | ||
[[Category: Edwards | [[Category: Edwards, T A]] | ||
[[Category: Hegedus Z]] | [[Category: Hegedus, Z]] | ||
[[Category: Hobor F]] | [[Category: Hobor, F]] | ||
[[Category: Lian | [[Category: Lian, L J]] | ||
[[Category: Sessions | [[Category: Sessions, R B]] | ||
[[Category: Shoemark | [[Category: Shoemark, D K]] | ||
[[Category: Trinh | [[Category: Trinh, C H]] | ||
[[Category: Wilson | [[Category: Wilson, A J]] | ||
[[Category: Beta-sheets acylhydrazone]] | |||
[[Category: Fragment-based drug discovery]] | |||
[[Category: Hybrid structure]] | |||
[[Category: Pdz domain]] | |||
[[Category: Peptide binding protein]] | |||
[[Category: Protein protein interaction]] | |||
