2QUZ

Crystal Structure of the activating H-RasK117R mutant in Costello Syndrome, bound to Mg-GDP

2QUZ の概要

• エントリーDOI: 10.2210/pdb2quz/pdb
• 分子名称: GTPase HRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: hydrolase, gtpase protein, costello syndrome, ras protein, signaling protein
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Lipid-anchor; Cytoplasmic side: P01112
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19370.71

構造登録者

Parret, A.,Scheffzek, K. (登録日: 2007-08-07, 公開日: 2007-12-11, 最終更新日: 2023-08-30)

主引用文献

Denayer, E.,Parret, A.,Chmara, M.,Schubbert, S.,Vogels, A.,Devriendt, K.,Frijns, J.P.,Rybin, V.,de Ravel, T.J.,Shannon, K.,Cools, J.,Scheffzek, K.,Legius, E.
Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.
Hum.Mutat., 29:232-239, 2008

PubMed Abstract: Costello syndrome is a mental retardation syndrome characterized by high birth weight, postnatal growth retardation, coarse face, loose skin, cardiovascular problems, and tumor predisposition. De novo heterozygous missense mutations in HRAS codon 12 and 13 disturbing the intrinsic GTP hydrolysis cause Costello syndrome. We report a patient with typical Costello syndrome and a novel heterozygous missense mutation in codon 117 (c.350A>G, p.Lys117Arg) of the HRAS gene, resulting in constitutive activation of the RAS/MAPK pathway similar to the typical p.Gly12Ser and p.Gly12Ala mutations. Recombinant HRAS p.Lys117Arg demonstrates normal intrinsic GTP hydrolysis and responsiveness to GTPase-activating proteins, but the nucleotide dissociation rate is increased 80-fold. Consistent with the biochemical data, the crystal structure of the p.Lys117Arg mutant indicates an altered interaction pattern of the side chain that is associated with unfavorable nucleotide binding properties. Together, these data show that a RAS mutation that only perturbs guanine nucleotide binding has similar functional consequences as mutations that impair GTP hydrolysis and causes human disease.

PubMed: 17979197
DOI: 10.1002/humu.20616

実験手法

X-RAY DIFFRACTION (1.49 Å)