Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target.

Škerlová J, Unterlass J, Göttmann M, Marttila P, Homan E, Helleday T, Jemth AS, Stenmark P

J. Biol. Chem. 295 (33) 11656-11668 [2020-08-14; online 2020-06-22]

The bifunctional human enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) catalyzes two essential steps in the de novo purine biosynthesis pathway. PAICS is overexpressed in many cancers and could be a promising target for the development of cancer therapeutics. Here, using gene knockdowns and clonogenic survival and cell viability assays, we demonstrate that PAICS is required for growth and survival of prostate cancer cells. PAICS catalyzes the carboxylation of aminoimidazole ribonucleotide (AIR) and the subsequent conversion of carboxyaminoimidazole ribonucleotide (CAIR) and l-aspartate to N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR). Of note, we present the first structures of human octameric PAICS in complexes with native ligands. In particular, we report the structure of PAICS with CAIR bound in the active sites of both domains and SAICAR bound in one of the SAICAR synthetase domains. Moreover, we report the PAICS structure with SAICAR and an ATP analog occupying the SAICAR synthetase active site. These structures provide insight into substrate and product binding and the architecture of the active sites, disclosing important structural information for rational design of PAICS inhibitors as potential anticancer drugs.

Protein Science Facility (PSF) [Service]

PubMed 32571877

DOI 10.1074/jbc.RA120.013695

Crossref 10.1074/jbc.RA120.013695

pii: S0021-9258(17)48465-1
pmc: PMC7450103
PDB: 5clj
PDB: 2h31
PDB: 4ja0
PDB: 3rgg
PDB: 2nsl
PDB: 2gqs
PDB: 4fe2
PDB: 4o7w
PDB: 2z02
PDB: 2cnv
PDB: 2cnu
PDB: 1obd