6YB8

Human octameric PAICS in complex with CAIR and SAICAR

Summary for 6YB8

• Entry DOI: 10.2210/pdb6yb8/pdb
• Related: 6yb9
• Descriptor: Multifunctional protein ADE2, 5-AMINO-1-(5-O-PHOSPHONO-BETA-D-RIBOFURANOSYL)-1H-IMIDAZOLE-4-CARBOXYLIC ACID, (2~{S})-2-[[5-azanyl-1-[(2~{R},3~{R},4~{S},5~{R})-3,4-bis(oxidanyl)-5-(phosphonooxymethyl)oxolan-2-yl]imidazol-4-yl]car bonylamino]butanedioic acid, ... (6 entities in total)
• Functional Keywords: de novo purine biosynthesis, nucleotide metabolism, cancer target, biosynthetic protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 96500.92

Authors

Skerlova, J.,Unterlass, J.,Gottmann, M.,Homan, E.,Helleday, T.,Jemth, A.S.,Stenmark, P. (deposition date: 2020-03-16, release date: 2020-07-08, Last modification date: 2024-01-24)

Primary citation

Skerlova, J.,Unterlass, J.,Gottmann, M.,Marttila, P.,Homan, E.,Helleday, T.,Jemth, A.S.,Stenmark, P.
Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target.
J.Biol.Chem., 295:11656-11668, 2020

PubMed Abstract: The bifunctional human enzyme phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS) catalyzes two essential steps in the 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 -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.

PubMed: 32571877
DOI: 10.1074/jbc.RA120.013695

Experimental method

X-RAY DIFFRACTION (2.36 Å)