5DOT

Crystal Structure of Human Carbamoyl phosphate synthetase I (CPS1), apo form

Summary for 5DOT

• Entry DOI: 10.2210/pdb5dot/pdb
• Descriptor: Carbamoyl-phosphate synthase [ammonia], mitochondrial, NICKEL (II) ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: carbamoyl phosphate synthase (ammonia utilizing), carbamoyl phosphate, ammonia, n-acetyl-l-glutamate, adenosine triphosphate, apo, urea cycle, ligase, multi-domain, allosteric site, rare disease, cps1 deficiency, hyperammonemia
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion : P31327
• Total number of polymer chains: 2
• Total formula weight: 328919.70

Authors

Polo, L.M.,de Cima, S.,Fita, I.,Rubio, V. (deposition date: 2015-09-11, release date: 2015-12-09, Last modification date: 2024-01-10)

Primary citation

de Cima, S.,Polo, L.M.,Diez-Fernandez, C.,Martinez, A.I.,Cervera, J.,Fita, I.,Rubio, V.
Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis.
Sci Rep, 5:16950-16950, 2015

PubMed Abstract: Human carbamoyl phosphate synthetase (CPS1), a 1500-residue multidomain enzyme, catalyzes the first step of ammonia detoxification to urea requiring N-acetyl-L-glutamate (NAG) as essential activator to prevent ammonia/amino acids depletion. Here we present the crystal structures of CPS1 in the absence and in the presence of NAG, clarifying the on/off-switching of the urea cycle by NAG. By binding at the C-terminal domain of CPS1, NAG triggers long-range conformational changes affecting the two distant phosphorylation domains. These changes, concerted with the binding of nucleotides, result in a dramatic remodeling that stabilizes the catalytically competent conformation and the building of the ~35 Å-long tunnel that allows migration of the carbamate intermediate from its site of formation to the second phosphorylation site, where carbamoyl phosphate is produced. These structures allow rationalizing the effects of mutations found in patients with CPS1 deficiency (presenting hyperammonemia, mental retardation and even death), as exemplified here for some mutations.

PubMed: 26592762
DOI: 10.1038/srep16950

Experimental method

X-RAY DIFFRACTION (2.4 Å)