5enb: Difference between revisions
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==Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with o-Tolylthiourea (SGC - Diamond I04-1 fragment screening)== | |||
<StructureSection load='5enb' size='340' side='right'caption='[[5enb]], [[Resolution|resolution]] 1.73Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5enb]] is a 1 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=5ENB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ENB 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]] 1.73Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5Q5:1-(2-METHYLPHENYL)THIOUREA'>5Q5</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5enb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enb OCA], [https://pdbe.org/5enb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5enb RCSB], [https://www.ebi.ac.uk/pdbsum/5enb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5enb ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PHIP_HUMAN PHIP_HUMAN] Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization.<ref>PMID:12242307</ref> <ref>PMID:21834987</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data. | |||
A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.,Cox OB, Krojer T, Collins P, Monteiro O, Talon R, Bradley A, Fedorov O, Amin J, Marsden BD, Spencer J, von Delft F, Brennan PE Chem Sci. 2016 Mar 1;7(3):2322-2330. doi: 10.1039/c5sc03115j. Epub 2015 Dec 22. PMID:29910922<ref>PMID:29910922</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5enb" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Bountra | ==See Also== | ||
[[Category: | *[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: | [[Category: Bradley A]] | ||
[[Category: Brennan P]] | |||
[[Category: Burgess-Brown N]] | |||
[[Category: Collins P]] | |||
[[Category: Cox O]] | |||
[[Category: Edwards A]] | |||
[[Category: Krojer T]] | |||
[[Category: Szykowska A]] | |||
[[Category: Talon R]] | |||
[[Category: Von Delft F]] | |||
Latest revision as of 11:08, 12 July 2023
Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with o-Tolylthiourea (SGC - Diamond I04-1 fragment screening)Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with o-Tolylthiourea (SGC - Diamond I04-1 fragment screening)
Structural highlights
FunctionPHIP_HUMAN Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization.[1] [2] Publication Abstract from PubMedResearch into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain.,Cox OB, Krojer T, Collins P, Monteiro O, Talon R, Bradley A, Fedorov O, Amin J, Marsden BD, Spencer J, von Delft F, Brennan PE Chem Sci. 2016 Mar 1;7(3):2322-2330. doi: 10.1039/c5sc03115j. Epub 2015 Dec 22. PMID:29910922[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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