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Crystal structures ...
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Škerlová, JanaStockholm University,Stockholms universitet,Institutionen för biokemi och biofysik
(author)
Crystal structures of human PAICS reveal substrate and product binding of an emerging cancer target
- Article/chapterEnglish2020
Publisher, publication year, extent ...
Numbers
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LIBRIS-ID:oai:DiVA.org:su-186671
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https://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-186671URI
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https://doi.org/10.1074/jbc.RA120.013695DOI
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https://lup.lub.lu.se/record/bbd72179-f41c-43f5-ae48-292a6ed7c253URI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:144566843URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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.
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Added entries (persons, corporate bodies, meetings, titles ...)
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Unterlass, JudithKarolinska Institute
(author)
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Göttmann, MonaKarolinska Institute
(author)
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Marttila, PetraKarolinska Institute
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Homan, EvertKarolinska Institutet,Karolinska Institute
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Helleday, ThomasKarolinska Institutet
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Jemth, Ann-SofieKarolinska Institutet,Karolinska Institute
(author)
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Stenmark, PålStockholm 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(Swepub:lu)pa4463st
(author)
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Stockholms universitetInstitutionen för biokemi och biofysik
(creator_code:org_t)
Related titles
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In:Journal of Biological Chemistry295:33, s. 11656-116680021-92581083-351X
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