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5enc

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Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with N-(2,6-Dichlorobenzyl)acetamide (SGC - Diamond I04-1 fragment screening)

Structural highlights

5enc is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.59Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Farhang-Fallah J, Randhawa VK, Nimnual A, Klip A, Bar-Sagi D, Rozakis-Adcock M. The pleckstrin homology (PH) domain-interacting protein couples the insulin receptor substrate 1 PH domain to insulin signaling pathways leading to mitogenesis and GLUT4 translocation. Mol Cell Biol. 2002 Oct;22(20):7325-36. PMID:12242307
↑ Bai SW, Herrera-Abreu MT, Rohn JL, Racine V, Tajadura V, Suryavanshi N, Bechtel S, Wiemann S, Baum B, Ridley AJ. Identification and characterization of a set of conserved and new regulators of cytoskeletal organization, cell morphology and migration. BMC Biol. 2011 Aug 11;9:54. doi: 10.1186/1741-7007-9-54. PMID:21834987 doi:10.1186/1741-7007-9-54
↑ 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. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Chem Sci. 2016 Mar 1;7(3):2322-2330. doi: 10.1039/c5sc03115j. Epub 2015 Dec 22. PMID:29910922 doi:http://dx.doi.org/10.1039/c5sc03115j

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5enc"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with N-(2,6-Dichlorobenzyl)acetamide (SGC - Diamond I04-1 fragment screening)==
-<StructureSection load='5enc' size='340' side='right' caption='[[5enc]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
+<StructureSection load='5enc' size='340' side='right'caption='[[5enc]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5enc]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ENC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ENC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5enc]] 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=5ENC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ENC FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5QD:~{N}-[[2,6-BIS(CHLORANYL)PHENYL]METHYL]ETHANAMIDE'>5QD</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 1.59&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PHIP, WDR11 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QD:~{N}-[[2,6-BIS(CHLORANYL)PHENYL]METHYL]ETHANAMIDE'>5QD</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5enc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enc OCA], [http://pdbe.org/5enc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5enc RCSB], [http://www.ebi.ac.uk/pdbsum/5enc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5enc 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=5enc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enc OCA], [https://pdbe.org/5enc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5enc RCSB], [https://www.ebi.ac.uk/pdbsum/5enc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5enc ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5enc" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Arrowsmith, C H]]
+[[Category: Large Structures]]
-[[Category: Bountra, C]]
+[[Category: Arrowsmith CH]]
-[[Category: Bradley, A]]
+[[Category: Bountra C]]
-[[Category: Brennan, P]]
+[[Category: Bradley A]]
-[[Category: Burgess-Brown, N]]
+[[Category: Brennan P]]
-[[Category: Collins, P]]
+[[Category: Burgess-Brown N]]
-[[Category: Cox, O]]
+[[Category: Collins P]]
-[[Category: Delft, F von]]
+[[Category: Cox O]]
-[[Category: Edwards, A]]
+[[Category: Edwards A]]
-[[Category: Krojer, T]]
+[[Category: Krojer T]]
-[[Category: Structural genomic]]
+[[Category: Szykowska A]]
-[[Category: Szykowska, A]]
+[[Category: Talon R]]
-[[Category: Talon, R]]
+[[Category: Von Delft F]]
-[[Category: Bromodomain]]
-[[Category: Crystallographic fragment screen]]
-[[Category: Phip]]
-[[Category: Sgc]]
-[[Category: Signaling protein]]
-[[Category: Transcription]]

5enc

From Proteopedia

Current revision

Crystal structure of the second bromodomain of Pleckstrin homology domain interacting protein (PHIP) in complex with N-(2,6-Dichlorobenzyl)acetamide (SGC - Diamond I04-1 fragment screening)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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