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Molecular mechanism of ATP versus GTP selectivity of adenylate kinase
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 12, p. 3012-3017Article in journal (Refereed) Published
Abstract [en]

Enzymatic substrate selectivity is critical for the precise control of metabolic pathways. In cases where chemically related substrates are present inside cells, robust mechanisms of substrate selectivity are required. Here, we report the mechanism utilized for catalytic ATP versus GTP selectivity during adenylate kinase (Adk) -mediated phosphorylation of AMP. Using NMR spectroscopy we found that while Adk adopts a catalytically competent and closed structural state in complex with ATP, the enzyme is arrested in a catalytically inhibited and open state in complex with GTP. X-ray crystallography experiments revealed that the interaction interfaces supporting ATP and GTP recognition, in part, are mediated by coinciding residues. The mechanism provides an atomic view on how the cellular GTP pool is protected from Adk turnover, which is important because GTP has many specialized cellular functions. In further support of this mechanism, a structure-function analysis enabled by synthesis of ATP analogs suggests that a hydrogen bond between the adenine moiety and the backbone of the enzyme is vital for ATP selectivity. The importance of the hydrogen bond for substrate selectivity is likely general given the conservation of its location and orientation across the family of eukaryotic protein kinases.

Place, publisher, year, edition, pages
2018. Vol. 115, no 12, p. 3012-3017
Keywords [en]
adenylate kinase, selectivity, ATP, GTP, mechanism
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-145883DOI: 10.1073/pnas.1721508115ISI: 000427829500063PubMedID: 29507216OAI: oai:DiVA.org:umu-145883DiVA, id: diva2:1191806
Available from: 2018-03-20 Created: 2018-03-20 Last updated: 2018-06-09Bibliographically approved

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Rogne, PerRosselin, MarieGrundström, ChristinHedberg, ChristianH. Sauer, UweWolf-Watz, Magnus

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