7lky

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of PHF1 Tudor domain in complex with a peptidomimetic ligand UNC6641

Structural highlights

7lky is a 16 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PHF1_HUMAN Transcriptional repressor. May promote methylation of histone H3 on 'Lys-27' by the PRC2/EED-EZH2 complex.^[1] ^[2]

Publication Abstract from PubMed

Plant homeodomain finger protein 1 (PHF1) is an accessory component of the gene silencing complex polycomb repressive complex 2 and recognizes the active chromatin mark, trimethylated lysine 36 of histone H3 (H3K36me3). In addition to its role in transcriptional regulation, PHF1 has been implicated as a driver of endometrial stromal sarcoma and fibromyxoid tumors. We report the discovery and characterization of UNC6641, a peptidomimetic antagonist of the PHF1 Tudor domain which was optimized through in silico modeling and incorporation of non-natural amino acids. UNC6641 binds the PHF1 Tudor domain with a K(d) value of 0.96 +/- 0.03 muM while also binding the related protein PHF19 with similar potency. A crystal structure of PHF1 in complex with UNC6641, along with NMR and site-directed mutagenesis data, provided insight into the binding mechanism and requirements for binding. Additionally, UNC6641 enabled the development of a high-throughput assay to identify small molecule binders of PHF1.

Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).,Engelberg IA, Liu J, Norris-Drouin JL, Cholensky SH, Ottavi SA, Frye SV, Kutateladze TG, James LI J Med Chem. 2021 Jun 24;64(12):8510-8522. doi: 10.1021/acs.jmedchem.1c00430. Epub , 2021 May 17. PMID:33999620^[3]

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

References

↑ Cao R, Wang H, He J, Erdjument-Bromage H, Tempst P, Zhang Y. Role of hPHF1 in H3K27 methylation and Hox gene silencing. Mol Cell Biol. 2008 Mar;28(5):1862-72. Epub 2007 Dec 17. PMID:18086877 doi:http://dx.doi.org/10.1128/MCB.01589-07
↑ Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol. 2008 Apr;28(8):2718-31. doi: 10.1128/MCB.02017-07. Epub 2008 Feb, 19. PMID:18285464 doi:10.1128/MCB.02017-07
↑ Engelberg IA, Liu J, Norris-Drouin JL, Cholensky SH, Ottavi SA, Frye SV, Kutateladze TG, James LI. Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1). J Med Chem. 2021 Jun 24;64(12):8510-8522. PMID:33999620 doi:10.1021/acs.jmedchem.1c00430

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7lky"

Categories: Homo sapiens | Large Structures | Synthetic construct | Kutateladze TG | Liu J

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 7lky is ON HOLD  until Paper Publication
+==Crystal Structure of PHF1 Tudor domain in complex with a peptidomimetic ligand UNC6641==
+<StructureSection load='7lky' size='340' side='right'caption='[[7lky]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[7lky]] is a 16 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=7LKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LKY 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]] 1.85&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=Y57:N~6~-(2-phenylethyl)-N~6~-propan-2-yl-L-lysine'>Y57</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7lky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lky OCA], [https://pdbe.org/7lky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lky RCSB], [https://www.ebi.ac.uk/pdbsum/7lky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lky ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/PHF1_HUMAN PHF1_HUMAN] Transcriptional repressor. May promote methylation of histone H3 on 'Lys-27' by the PRC2/EED-EZH2 complex.<ref>PMID:18086877</ref> <ref>PMID:18285464</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Plant homeodomain finger protein 1 (PHF1) is an accessory component of the gene silencing complex polycomb repressive complex 2 and recognizes the active chromatin mark, trimethylated lysine 36 of histone H3 (H3K36me3). In addition to its role in transcriptional regulation, PHF1 has been implicated as a driver of endometrial stromal sarcoma and fibromyxoid tumors. We report the discovery and characterization of UNC6641, a peptidomimetic antagonist of the PHF1 Tudor domain which was optimized through in silico modeling and incorporation of non-natural amino acids. UNC6641 binds the PHF1 Tudor domain with a K(d) value of 0.96 +/- 0.03 muM while also binding the related protein PHF19 with similar potency. A crystal structure of PHF1 in complex with UNC6641, along with NMR and site-directed mutagenesis data, provided insight into the binding mechanism and requirements for binding. Additionally, UNC6641 enabled the development of a high-throughput assay to identify small molecule binders of PHF1.
-Authors:
+Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).,Engelberg IA, Liu J, Norris-Drouin JL, Cholensky SH, Ottavi SA, Frye SV, Kutateladze TG, James LI J Med Chem. 2021 Jun 24;64(12):8510-8522. doi: 10.1021/acs.jmedchem.1c00430. Epub , 2021 May 17. PMID:33999620<ref>PMID:33999620</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 7lky" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Synthetic construct]]
+[[Category: Kutateladze TG]]
+[[Category: Liu J]]

7lky

From Proteopedia

Current revision

Crystal Structure of PHF1 Tudor domain in complex with a peptidomimetic ligand UNC6641

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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