4FLP

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

4FLP の概要

• エントリーDOI: 10.2210/pdb4flp/pdb
• 関連するPDBエントリー: 2RFJ
• 分子名称: Bromodomain testis-specific protein, (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, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: brdt, bromodomain containing protein testis specific, nucleus, transcription, transcription regulation, structural genomics consortium, sgc, bromodomain, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (Probable): Q58F21
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29287.94

構造登録者

Filippakopoulos, P.,Picaud, S.,Qi, J.,Felletar, I.,Canning, P.,Muniz, J.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Bradner, J.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2012-06-15, 公開日: 2012-07-11, 最終更新日: 2023-09-13)

主引用文献

Matzuk, M.M.,McKeown, M.R.,Filippakopoulos, P.,Li, Q.,Ma, L.,Agno, J.E.,Lemieux, M.E.,Picaud, S.,Yu, R.N.,Qi, J.,Knapp, S.,Bradner, J.E.
Small-Molecule Inhibition of BRDT for Male Contraception.
Cell(Cambridge,Mass.), 150:673-684, 2012

PubMed Abstract: 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.

PubMed: 22901802
DOI: 10.1016/j.cell.2012.06.045

実験手法

X-RAY DIFFRACTION (2.23 Å)