Common Mechanism of Activated Catalysis in P-loop Fold Nucleoside Triphosphatases—United in Diversity

Autor: Maria I. Kozlova, Daria N. Shalaeva, Daria V. Dibrova, Armen Y. Mulkidjanian
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Biomolecules, Vol 12, Iss 10, p 1346 (2022)
Druh dokumentu: article
ISSN: 12101346
2218-273X
DOI: 10.3390/biom12101346
Popis: To clarify the obscure hydrolysis mechanism of ubiquitous P-loop-fold nucleoside triphosphatases (Walker NTPases), we analysed the structures of 3136 catalytic sites with bound Mg-NTP complexes or their analogues. Our results are presented in two articles; here, in the second of them, we elucidated whether the Walker A and Walker B sequence motifs—common to all P-loop NTPases—could be directly involved in catalysis. We found that the hydrogen bonds (H-bonds) between the strictly conserved, Mg-coordinating Ser/Thr of the Walker A motif ([Ser/Thr]WA) and aspartate of the Walker B motif (AspWB) are particularly short (even as short as 2.4 ångströms) in the structures with bound transition state (TS) analogues. Given that a short H-bond implies parity in the pKa values of the H-bond partners, we suggest that, in response to the interactions of a P-loop NTPase with its cognate activating partner, a proton relocates from [Ser/Thr]WA to AspWB. The resulting anionic [Ser/Thr]WA alkoxide withdraws a proton from the catalytic water molecule, and the nascent hydroxyl attacks the gamma phosphate of NTP. When the gamma-phosphate breaks away, the trapped proton at AspWB passes by the Grotthuss relay via [Ser/Thr]WA to beta-phosphate and compensates for its developing negative charge that is thought to be responsible for the activation barrier of hydrolysis.
Databáze: Directory of Open Access Journals
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