8UWP

Crystal structure of SETDB1 Tudor domain in complex with MR46747

8UWP の概要

• エントリーDOI: 10.2210/pdb8uwp/pdb
• 分子名称: Histone-lysine N-methyltransferase SETDB1, (3S)-N-(4-chloro-3-{[2-(diethylamino)ethyl]carbamoyl}phenyl)-3-(diethylamino)pyrrolidine-1-carboxamide, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: setdb1, epigenetics, methyllysine reader, sgc, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 54747.77

構造登録者

Shrestha, S.,Beldar, S.,Dong, A.,Ackloo, S.,Brown, P.J.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2023-11-07, 公開日: 2023-11-22, 最終更新日: 2025-06-04)

主引用文献

Ackloo, S.,Li, F.,Szewczyk, M.,Seitova, A.,Loppnau, P.,Zeng, H.,Xu, J.,Ahmad, S.,Arnautova, Y.A.,Baghaie, A.J.,Beldar, S.,Bolotokova, A.,Centrella, P.A.,Chau, I.,Clark, M.A.,Cuozzo, J.W.,Dehghani-Tafti, S.,Disch, J.S.,Dong, A.,Dumas, A.,Feng, J.A.,Ghiabi, P.,Gibson, E.,Gilmer, J.,Goldman, B.,Green, S.R.,Guie, M.A.,Guilinger, J.P.,Harms, N.,Herasymenko, O.,Houliston, S.,Hutchinson, A.,Kearnes, S.,Keefe, A.D.,Kimani, S.W.,Kramer, T.,Kutera, M.,Kwak, H.A.,Lento, C.,Li, Y.,Liu, J.,Loup, J.,Machado, R.A.C.,Mulhern, C.J.,Perveen, S.,Righetto, G.L.,Riley, P.,Shrestha, S.,Sigel, E.A.,Silva, M.,Sintchak, M.D.,Slakman, B.L.,Taylor, R.D.,Thompson, J.,Torng, W.,Underkoffler, C.,von Rechenberg, M.,Walsh, R.T.,Watson, I.,Wilson, D.J.,Wolf, E.,Yadav, M.,Yazdi, A.K.,Zhang, J.,Zhang, Y.,Santhakumar, V.,Edwards, A.M.,Barsyte-Lovejoy, D.,Schapira, M.,Brown, P.J.,Halabelian, L.,Arrowsmith, C.H.
A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.
J.Med.Chem., 68:1092-1112, 2025

PubMed Abstract: Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.

PubMed: 39495097
DOI: 10.1021/acs.jmedchem.4c02010

実験手法

X-RAY DIFFRACTION (1.77 Å)