6UEL

CPS1 bound to allosteric inhibitor H3B-193

Summary for 6UEL

• Entry DOI: 10.2210/pdb6uel/pdb
• Descriptor: Carbamoyl-phosphate synthase [ammonia], mitochondrial, ZINC ION, N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide, ... (4 entities in total)
• Functional Keywords: allosteric inhibitor, cps1, ligase, transferase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 331168.83

Authors

Larsen, N.A.,Nguyen, T.V. (deposition date: 2019-09-21, release date: 2020-03-18, Last modification date: 2023-10-11)

Primary citation

Yao, S.,Nguyen, T.V.,Rolfe, A.,Agrawal, A.A.,Ke, J.,Peng, S.,Colombo, F.,Yu, S.,Bouchard, P.,Wu, J.,Huang, K.C.,Bao, X.,Omoto, K.,Selvaraj, A.,Yu, L.,Ioannidis, S.,Vaillancourt, F.H.,Zhu, P.,Larsen, N.A.,Bolduc, D.M.
Small Molecule Inhibition of CPS1 Activity through an Allosteric Pocket.
Cell Chem Biol, 27:259-268.e5, 2020

PubMed Abstract: Carbamoyl phosphate synthetase 1 (CPS1) catalyzes the first step in the ammonia-detoxifying urea cycle, converting ammonia to carbamoyl phosphate under physiologic conditions. In cancer, CPS1 overexpression supports pyrimidine synthesis to promote tumor growth in some cancer types, while in others CPS1 activity prevents the buildup of toxic levels of intratumoral ammonia to allow for sustained tumor growth. Targeted CPS1 inhibitors may, therefore, provide a therapeutic benefit for cancer patients with tumors overexpressing CPS1. Herein, we describe the discovery of small-molecule CPS1 inhibitors that bind to a previously unknown allosteric pocket to block ATP hydrolysis in the first step of carbamoyl phosphate synthesis. CPS1 inhibitors are active in cellular assays, blocking both urea synthesis and CPS1 support of the pyrimidine biosynthetic pathway, while having no activity against CPS2. These newly discovered CPS1 inhibitors are a first step toward providing researchers with valuable tools for probing CPS1 cancer biology.

PubMed: 32017919
DOI: 10.1016/j.chembiol.2020.01.009

Experimental method

X-RAY DIFFRACTION (1.9 Å)