6yx2: Difference between revisions

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'''Unreleased structure'''


The entry 6yx2 is ON HOLD
==Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid==
<StructureSection load='6yx2' size='340' side='right'caption='[[6yx2]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6yx2]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YX2 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]] 1.62&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PWW:4-[[(~{E})-5-oxidanylidenepentanoyldiazenyl]methyl]benzoic+acid'>PWW</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=6yx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yx2 OCA], [https://pdbe.org/6yx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yx2 RCSB], [https://www.ebi.ac.uk/pdbsum/6yx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yx2 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.


Authors: Hegedus, Z., Hobor, F., Shoemark, D.K., Celis, S., Lian, L.J., Trinh, C.H., Sessions, R.B., Edwards, T.A., Wilson, A.J.
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>


Description: Crystal structure of SHANK1 PDZ in complex with a peptide-small molecule hybrid
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
[[Category: Hegedus, Z]]
<div class="pdbe-citations 6yx2" style="background-color:#fffaf0;"></div>
[[Category: Trinh, C.H]]
== References ==
[[Category: Shoemark, D.K]]
<references/>
[[Category: Hobor, F]]
__TOC__
[[Category: Celis, S]]
</StructureSection>
[[Category: Sessions, R.B]]
[[Category: Homo sapiens]]
[[Category: Lian, L.J]]
[[Category: Large Structures]]
[[Category: Edwards, T.A]]
[[Category: Synthetic construct]]
[[Category: Wilson, A.J]]
[[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]]
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