4flp

From Proteopedia

(Difference between revisions)

Revision as of 05:45, 5 August 2016

Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor JQ1

Structural highlights

4flp is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2rfj
Gene:	BRDT (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[BRDT_HUMAN] Testis-specific chromatin protein that specifically binds histone H4 acetylated at 'Lys-5' and 'Lys-8' (H4K5ac and H4K8ac, respectively) and plays a key role in spermatogenesis. Required in late pachytene spermatocytes: plays a role in meiotic and post-meiotic cells by binding to acetylated histones at the promoter of specific meiotic and post-meiotic genes, facilitating their activation at the appropriate time. In the post-meiotic phase of spermatogenesis, binds to hyperacetylated histones and participates in their general removal from DNA. Also acts as a component of the splicing machinery in pachytene spermatocytes and round spermatids and participates in 3'-UTR truncation of specific mRNAs in post-meiotic spermatids. Required for chromocenter organization, a structure comprised of peri-centromeric heterochromatin.^[1] ^[2] ^[3]

Publication Abstract from PubMed

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception. PAPERCLIP:

Small-Molecule Inhibition of BRDT for Male Contraception.,Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE Cell. 2012 Aug 17;150(4):673-684. PMID:22901802^[4]

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

References

↑ Jones MH, Numata M, Shimane M. Identification and characterization of BRDT: A testis-specific gene related to the bromodomain genes RING3 and Drosophila fsh. Genomics. 1997 Nov 1;45(3):529-34. PMID:9367677 doi:S0888-7543(97)95000-X
↑ Zheng Y, Yuan W, Zhou Z, Xu M, Sha JH. Molecular cloning and expression of a novel alternative splice variant of BRDT gene. Int J Mol Med. 2005 Feb;15(2):315-21. PMID:15647849
↑ Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE. Small-Molecule Inhibition of BRDT for Male Contraception. Cell. 2012 Aug 17;150(4):673-684. PMID:22901802 doi:10.1016/j.cell.2012.06.045
↑ Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE. Small-Molecule Inhibition of BRDT for Male Contraception. Cell. 2012 Aug 17;150(4):673-684. PMID:22901802 doi:10.1016/j.cell.2012.06.045

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/4flp"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor JQ1==
 <StructureSection load='4flp' size='340' side='right' caption='[[4flp]], [[Resolution|resolution]] 2.23&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4flp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FLP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FLP FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4flp]] is a 2 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=4FLP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FLP FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JQ1:(6S)-6-(2-TERT-BUTOXY-2-OXOETHYL)-4-(4-CHLOROPHENYL)-2,3,9-TRIMETHYL-6,7-DIHYDROTHIENO[3,2-F][1,2,4]TRIAZOLO[4,3-A][1,4]DIAZEPIN-10-IUM'>JQ1</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2rfj|2rfj]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRDT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BRDT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4flp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4flp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4flp RCSB], [http://www.ebi.ac.uk/pdbsum/4flp PDBsum]</span></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=4flp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4flp OCA], [http://pdbe.org/4flp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4flp RCSB], [http://www.ebi.ac.uk/pdbsum/4flp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4flp ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4flp" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Arrowsmith, C H]]
 [[Category: Bountra, C]]

4flp

From Proteopedia

Revision as of 05:45, 5 August 2016

Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor JQ1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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