5URM

Crystal structure of human BRR2 in complex with T-1206548

Summary for 5URM

• Entry DOI: 10.2210/pdb5urm/pdb
• Related: 5URJ 5URK
• Descriptor: U5 small nuclear ribonucleoprotein 200 kDa helicase, 3-(5-{[(2R)-5-amino-2-cyclohexyl-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-6-yl]methyl}furan-2-yl)benzoic acid (3 entities in total)
• Functional Keywords: brr2 inhibitor, rna helicase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : O75643
• Total number of polymer chains: 2
• Total formula weight: 398070.18

Authors

Klein, M.G.,Tjhen, R.,Qin, L. (deposition date: 2017-02-11, release date: 2017-07-19, Last modification date: 2024-03-06)

Primary citation

Iwatani-Yoshihara, M.,Ito, M.,Klein, M.G.,Yamamoto, T.,Yonemori, K.,Tanaka, T.,Miwa, M.,Morishita, D.,Endo, S.,Tjhen, R.,Qin, L.,Nakanishi, A.,Maezaki, H.,Kawamoto, T.
Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2.
J. Med. Chem., 60:5759-5771, 2017

PubMed Abstract: Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2.

PubMed: 28586220
DOI: 10.1021/acs.jmedchem.7b00461

Experimental method

X-RAY DIFFRACTION (2.8 Å)