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Crystal structures ...
Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target
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- Škerlová, Jana (författare)
- Stockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
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- Unterlass, Judith (författare)
- Karolinska Institute
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- Göttmann, Mona (författare)
- Karolinska Institute
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- Marttila, Petra (författare)
- Karolinska Institute
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- Homan, Evert (författare)
- Karolinska Institutet,Karolinska Institute
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- Helleday, Thomas (författare)
- Karolinska Institutet
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- Jemth, Ann-Sofie (författare)
- Karolinska Institutet,Karolinska Institute
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- Stenmark, Pål (författare)
- Stockholm University,Lunds universitet,Stockholms universitet,Institutionen för biokemi och biofysik,Lund University, Sweden,Strukturell biokemi,Forskargrupper vid Lunds universitet,Structural Biochemistry,Lund University Research Groups
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(creator_code:org_t)
- 2020
- 2020
- Engelska.
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:33, s. 11656-11668
- Relaterad länk:
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https://doi.org/10.1...
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- de novo purine biosynthesis
- nucleotide metabolism
- cancer target
- rational drug design
- carboxyaminoimidazole ribonucleotide (CAIR)
- N-succinylcarboxamide-5-aminoimidazole ribonucleotide (SAICAR)
- phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthetase (PAICS)
- prostate cancer
- structural biology
- purine
- cancer therapy
- drug design
- nucleoside
- nucleotide biosynthesis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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