6pg7

From Proteopedia

(Difference between revisions)

Current revision

WDR5delta32 bound to (2-(3-methoxy-3-phenylpropyl)-1H-imidazol-4-yl)methanol

Structural highlights

6pg7 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 2.45Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

WDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 A) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k d = approximately 0.06 s(-1)) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.

Fragment screening for a protein-protein interaction inhibitor to WDR5.,Dennis ML, Morrow BJ, Dolezal O, Cuzzupe AN, Stupple AE, Newman J, Bentley J, Hattarki M, Nuttall SD, Foitzik RC, Street IP, Stupple PA, Monahan BJ, Peat TS Struct Dyn. 2019 Nov 14;6(6):064701. doi: 10.1063/1.5122849. eCollection 2019, Nov. PMID:31768400^[6]

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

References

↑ Patel A, Dharmarajan V, Vought VE, Cosgrove MS. On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. J Biol Chem. 2009 Sep 4;284(36):24242-56. Epub 2009 Jun 25. PMID:19556245 doi:M109.014498
↑ Guelman S, Kozuka K, Mao Y, Pham V, Solloway MJ, Wang J, Wu J, Lill JR, Zha J. The double-histone-acetyltransferase complex ATAC is essential for mammalian development. Mol Cell Biol. 2009 Mar;29(5):1176-88. doi: 10.1128/MCB.01599-08. Epub 2008 Dec, 22. PMID:19103755 doi:10.1128/MCB.01599-08
↑ Cai Y, Jin J, Swanson SK, Cole MD, Choi SH, Florens L, Washburn MP, Conaway JW, Conaway RC. Subunit composition and substrate specificity of a MOF-containing histone acetyltransferase distinct from the male-specific lethal (MSL) complex. J Biol Chem. 2010 Feb 12;285(7):4268-72. doi: 10.1074/jbc.C109.087981. Epub 2009 , Dec 14. PMID:20018852 doi:10.1074/jbc.C109.087981
↑ Han Z, Guo L, Wang H, Shen Y, Deng XW, Chai J. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol Cell. 2006 Apr 7;22(1):137-44. PMID:16600877 doi:10.1016/j.molcel.2006.03.018
↑ Couture JF, Collazo E, Trievel RC. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat Struct Mol Biol. 2006 Aug;13(8):698-703. Epub 2006 Jul 9. PMID:16829960 doi:10.1038/nsmb1116
↑ Dennis ML, Morrow BJ, Dolezal O, Cuzzupe AN, Stupple AE, Newman J, Bentley J, Hattarki M, Nuttall SD, Foitzik RC, Street IP, Stupple PA, Monahan BJ, Peat TS. Fragment screening for a protein-protein interaction inhibitor to WDR5. Struct Dyn. 2019 Nov 14;6(6):064701. doi: 10.1063/1.5122849. eCollection 2019, Nov. PMID:31768400 doi:http://dx.doi.org/10.1063/1.5122849

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/6pg7"

Categories: Homo sapiens | Large Structures | Dennis ML | Peat TS

@@ Line 3: / Line 3: @@
 <StructureSection load='6pg7' size='340' side='right'caption='[[6pg7]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pg7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PG7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PG7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pg7]] 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=6PG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PG7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OH4:{2-[(3S)-3-methoxy-3-phenylpropyl]-1H-imidazol-4-yl}methanol'>OH4</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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]] 2.45&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6pg3|6pg3]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OH4:{2-[(3S)-3-methoxy-3-phenylpropyl]-1H-imidazol-4-yl}methanol'>OH4</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=6pg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pg7 OCA], [http://pdbe.org/6pg7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pg7 RCSB], [http://www.ebi.ac.uk/pdbsum/6pg7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pg7 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=6pg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pg7 OCA], [https://pdbe.org/6pg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pg7 RCSB], [https://www.ebi.ac.uk/pdbsum/6pg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pg7 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN]] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref>
+[https://www.uniprot.org/uniprot/WDR5_HUMAN WDR5_HUMAN] Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.<ref>PMID:19556245</ref> <ref>PMID:19103755</ref> <ref>PMID:20018852</ref> <ref>PMID:16600877</ref> <ref>PMID:16829960</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6pg7" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[WD-repeat protein 3D structures|WD-repeat protein 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Dennis, M L]]
+[[Category: Dennis ML]]
-[[Category: Peat, T S]]
+[[Category: Peat TS]]
-[[Category: B-propellor]]
-[[Category: Chromatin regulator]]
-[[Category: Inhibitor]]
-[[Category: Protein binding]]
-[[Category: Protein binding-inhibitor complex]]
-[[Category: Scaffolding protein]]

6pg7

From Proteopedia

Current revision

WDR5delta32 bound to (2-(3-methoxy-3-phenylpropyl)-1H-imidazol-4-yl)methanol

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox