期刊
STRUCTURE
卷 24, 期 4, 页码 617-623出版社
CELL PRESS
DOI: 10.1016/j.str.2016.02.018
关键词
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资金
- Lundbeck Foundation
- Danish Medical Research Council
- Novo Nordisk/Vilhelm Pedersen Foundation
- Danish Council for Strategic Research
- Lundbeck Foundation [R93-2011-8682] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0011639, NNF12OC0002082] Funding Source: researchfish
Vanadate is the hallmark inhibitor of the P-type ATPase family; however, structural details of its inhibitory mechanism have remained unresolved. We have determined the crystal structure of sarcoplasmic reticulum Ca2+-ATPase with bound vanadate in the absence of Ca2+. Vanadate is bound at the catalytic site as a planar VO3- in complex with water and Mg2+ in a dephosphorylation transition-state-like conformation. Validating bound VO3- by anomalous difference Fourier maps using long-wavelength data we also identify a hitherto undescribed Cl- site near the dephosphorylation site. Crystallization was facilitated by trinitrophenyl (TNP)-derivatized nucleotides that bind with the TNP moiety occupying the binding pocket that normally accommodates the adenine of ATP, rationalizing their remarkably high affinity for E2P-like conformations of the Ca2+-ATPase. A comparison of the configurations of bound nucleotide analogs in the E2 center dot VO3- structure with that in E2 center dot BeF3- (E2P ground state analog) reveals multiple binding modes to the Ca2+-ATPase.
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