8UWP

Crystal structure of SETDB1 Tudor domain in complex with MR46747

Summary for 8UWP

• Entry DOI: 10.2210/pdb8uwp/pdb
• Descriptor: 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)
• Functional Keywords: setdb1, epigenetics, methyllysine reader, sgc, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 54747.77

Authors

Shrestha, S.,Beldar, S.,Dong, A.,Ackloo, S.,Brown, P.J.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (deposition date: 2023-11-07, release date: 2023-11-22, Last modification date: 2025-06-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.77 Å)