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19F NMR and DFT analysis reveal structural and electronic transition state features for RhoA-catalyzed GTP hydrolysis

Jin, Yi, Molt Jr, Robert W., Waltho, Jonathan P., Richards, Nigel G. J. and Blackburn, G. Michael 2016. 19F NMR and DFT analysis reveal structural and electronic transition state features for RhoA-catalyzed GTP hydrolysis. Angewandte Chemie International Edition 55 (10) , pp. 3318-3322. 10.1002/anie.201509477

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Molecular details for RhoA/GAP catalysis of the hydrolysis of GTP to GDP are poorly understood. We use 19F NMR chemical shifts in the MgF3− transition state analogue (TSA) complex as a spectroscopic reporter to indicate electron distribution for the γ-PO3− oxygens in the corresponding TS, implying that oxygen coordinated to Mg has the greatest electron density. This was validated by QM calculations giving a picture of the electronic properties of the transition state (TS) for nucleophilic attack of water on the γ-PO3− group based on the structure of a RhoA/GAP-GDP-MgF3− TSA complex. The TS model displays a network of 20 hydrogen bonds, including the GAP Arg85′ side chain, but neither phosphate torsional strain nor general base catalysis is evident. The nucleophilic water occupies a reactive location different from that in multiple ground state complexes, arising from reorientation of the Gln-63 carboxamide by Arg85′ to preclude direct hydrogen bonding from water to the target γ-PO3− group.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Uncontrolled Keywords: 19F NMR; enzyme catalysis; GTP hydrolases; phosphoryl transfer; reaction mechanisms
Publisher: Wiley
ISSN: 1433-7851
Date of First Compliant Deposit: 1 April 2016
Date of Acceptance: 20 January 2016
Last Modified: 28 Sep 2020 11:45

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