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  Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate

Ostermann, N., Schlichting, I., Brundiers, R., Konrad, M., Reinstein, J., Veit, T., et al. (2000). Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate. Structure, 8(6), 629-642. doi:10.1016/S0969-2126(00)00149-0.

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Alternativer Titel : Insights into the phosphoryltransfer mechanism of human thymidylate kinase gained from crystal structures of enzyme complexes along the reaction coordinate

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 Urheber:
Ostermann, Nils, Autor
Schlichting, Ilme1, Autor           
Brundiers, Ralf, Autor
Konrad, Manfred, Autor
Reinstein, Jochen1, Autor           
Veit, Thomas, Autor
Goody, Roger S.2, Autor           
Lavie, Amon, Autor
Affiliations:
1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              
2Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497712              

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Schlagwörter: Conformational change; Crystal structures; P loop; Thymidylate kinase
 Zusammenfassung: Background: Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes the reversible phosphoryltransfer between ATP and TMP to yield ADP and TDP. In addition to its vital role in supplying precursors for DNA synthesis, human TMPK has an important medical role participating in the activation of a number of anti-HIV prodrugs. Results: Crystal structures of human TMPK in complex with TMP and ADP, TMP and the ATP analog AppNHp, TMP with ADP and the phosphoryl analog AlF3, TDP and ADP, and the bisubstrate analog TP5A were determined. The conformations of the P-loop, the LID region, and the adenine-binding loop vary according to the nature of the complex. Substitution of ADP by AppNHp results in partial closure of the P-loop and the rotation of the TMP phosphate group to a catalytically unfavorable position, which rotates back in the AlF3 complex to a position suitable for in-line attack. In the fully closed state observed in the TP5A and the TDP–ADP complexes, Asp15 interacts strongly with the 3′-hydroxyl group of TMP. Conclusions: The observed changes of nucleotide state and conformation and the corresponding protein structural changes are correlated with intermediates occurring along the reaction coordinate and show the sequence of events occurring during phosphate transfer. The low catalytic activity of human TMPK appears to be determined by structural changes required to achieve catalytic competence and it is suggested that a mechanism might exist to accelerate the activity.

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Sprache(n): eng - English
 Datum: 2000-03-072000-02-102000-03-232000-06-162000-06-15
 Publikationsstatus: Erschienen
 Seiten: 14
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: eDoc: 666305
DOI: 10.1016/S0969-2126(00)00149-0
Anderer: 4808
 Art des Abschluß: -

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Titel: Structure
  Andere : Structure
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: London : Cell Press
Seiten: - Band / Heft: 8 (6) Artikelnummer: - Start- / Endseite: 629 - 642 Identifikator: ISSN: 0969-2126
CoNE: https://pure.mpg.de/cone/journals/resource/954927002244_1