1xtq
Structure of small GTPase human Rheb in complex with GDP
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OverviewOverview
The small GTPase Rheb displays unique biological and biochemical, properties different from other small GTPases and functions as an, important mediator between the tumor suppressor proteins TSC1 and TSC2 and, the mammalian target of rapamycin to stimulate cell growth. We report here, the three-dimensional structures of human Rheb in complexes with GDP, GTP, and GppNHp (5'-(beta,gamma-imide)triphosphate), which reveal novel, structural features of Rheb and provide a molecular basis for its distinct, properties. During GTP/GDP cycling, switch I of Rheb undergoes, conformational change while switch II maintains a stable, unusually, extended conformation, which is substantially different from the, alpha-helical conformation seen in other small GTPases. The unique switch, II conformation results in a displacement of Gln64 (equivalent to the, catalytic Gln61 of Ras), making it incapable of participating in GTP, hydrolysis and thus accounting for the low intrinsic GTPase activity of, Rheb. This rearrangement also creates space to accommodate the side chain, of Arg15, avoiding its steric hindrance with the catalytic residue and, explaining its noninvolvement in GTP hydrolysis. Unlike Ras, the phosphate, moiety of GTP in Rheb is shielded by the conserved Tyr35 of switch I, leading to the closure of the GTP-binding site, which appears to prohibit, the insertion of a potential arginine finger from its GTPase-activating, protein. Taking the genetic, biochemical, biological, and structural data, together, we propose that Rheb forms a new group of the Ras/Rap subfamily, and uses a novel GTP hydrolysis mechanism that utilizes Asn1643 of the, tuberous sclerosis complex 2 GTPase-activating protein domain instead of, Gln64 of Rheb as the catalytic residue.
About this StructureAbout this Structure
1XTQ is a Single protein structure of sequence from Homo sapiens with MG and GDP as ligands. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for the unique biological function of small GTPase RHEB., Yu Y, Li S, Xu X, Li Y, Guan K, Arnold E, Ding J, J Biol Chem. 2005 Apr 29;280(17):17093-100. Epub 2005 Feb 23. PMID:15728574
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