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

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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.


  • Jana Škerlová
  • Judith Unterlass
  • Mona Göttmann
  • Petra Marttila
  • Evert Homan
  • Thomas Helleday
  • Ann-Sofie Jemth
  • Pål Stenmark
External organisations
  • Stockholm University
  • Karolinska Institutet
  • University of Sheffield
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry
Original languageEnglish
Pages (from-to)11656-11668
JournalJournal of Biological Chemistry
Issue number33
Early online date2020 Jun 22
Publication statusPublished - 2020
Publication categoryResearch

Bibliographic note

Published under license by The American Society for Biochemistry and Molecular Biology, Inc.