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

DOI: 10.1074/jbc.RA120.013695

Authors: Jana Skerlova (Stockholm University) , Judith Unterlass (Karolinska Institutet) , Mona Göttmann (Karolinska Institutet) , Petra Marttila (Karolinska Institutet) , Evert Homan (Karolinska Institutet) , Thomas Helleday (University of Sheffield) , Ann-Sofie Jemth (Karolinska Institutet) , Pal Stenmark (Lund University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 15806

Abstract: 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.

Journal Keywords: de novo purine biosynthesis; cancer target; rational drug design; carboxyaminoimidazole ribonucleotide (CAIR); N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR); structural biology; drug design; cancer therapy; purine; nucleoside/nucleotide b

Diamond Keywords: Prostate Cancer; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 01/07/2020 11:24

Documents:
jbc.RA120.013695.full.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)