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Papers In Press, published online ahead of print November 13, 2002
J. Biol. Chem, 10.1074/jbc.M211042200
Submitted on October 29, 2002
Revised on November 12, 2002
Accepted on November 13, 2002

High resolution crystal structures of human Rab5a and five mutants with substitutions in the catalytically important phosphate-binding loop

Guangyu Zhu, Jian Liu, Simon Terzyan, Peng Zhai, Guangpu Li, and Xuejun C. Zhang

Crystallography Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

Corresponding Author: zhangc{at}omrf.ouhsc.edu

We report GTPase domain crystal structures of Rab5a wild-type and five variants with mutations in the phosphate-binding loop at resolutions up to 1.5 Å. Of particular interest, the A30P mutant was crystallized in complexes with GDP, GDP+AlF3 and authentic GTP, respectively. The other variant crystals were obtained in complexes with a non-hydrolysable GTP analog, GppNHp. All structures were solved in the same crystal form, providing an unusual opportunity to compare structures of small GTPases with different catalytic rates. The A30P mutant exhibits dramatically reduced GTPase activity and forms a GTP-bound complex stable enough for crystallographic analysis. Importantly, the A30P structure with bound GDP plus AlF3 has been solved in the absence of a GTPase activating protein (GAP). Since GDP and AlFx usually bind to small GTPases in the presence of a GAP and produce a transition-state mimic, the A30P structure may resemble that of a transition-state intermediate. Conformational changes are observed between the GTP-bound form and the transition-state intermediate, mainly in the switch II region containing the catalytic Gln79 residue and independent of A30P mutation-induced local alterations in the P-loop. The structures suggest an important catalytic role for a P-loop backbone amide group, which is eliminated in the A30P mutant, and support the notion that the transition state of GTPase-mediated GTP hydrolysis is of considerable dissociative character.


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