Sandbox Reserved 556
From Proteopedia
| This Sandbox is Reserved from 05/22/2012, through 07/22/2012 for use in the course "BIOL 414" taught by Greg Buhrman at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 551 through Sandbox Reserved 590. |
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Hi Jay, Here is your very own Proteopedia Page for pdb code: 3K8Y. Your presentation is scheduled for: June 20.
Have Fun!
Greg Buhrman
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| 3k8y, resolution 1.30Å () | |||||||||
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| Ligands: | , , , | ||||||||
| Gene: | HRAS, HRAS1 (Homo sapiens) | ||||||||
| Related: | 2rge, 3k9n, 3k9l | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Allosteric modulation of H-Ras GTPase
Ras and its effector Raf are key mediators of the Ras/Raf/MEK/ERK signal transduction pathway. Mutants of residue Q61 impair the GTPase activity of Ras and are found prominently in human cancers. Yet the mechanism through which Q61 contributes to catalysis has been elusive. It is thought to position the catalytic water molecule for nucleophilic attack on the gamma-phosphate of GTP. However, we previously solved the structure of Ras from crystals with symmetry of the space group R32 in which switch II is disordered and found that the catalytic water molecule is present. Here we present a structure of wild-type Ras with calcium acetate from the crystallization mother liquor bound at a site remote from the active site and likely near the membrane. This results in a shift in helix 3/loop 7 and a network of H-bonding interactions that propagates across the molecule, culminating in the ordering of switch II and placement of Q61 in the active site in a previously unobserved conformation. This structure suggests a direct catalytic role for Q61 where it interacts with a water molecule that bridges one of the gamma-phosphate oxygen atoms to the hydroxyl group of Y32 to stabilize the transition state of the hydrolysis reaction. We propose that Raf together with the binding of Ca(2+) and a negatively charged group mimicked in our structure by the acetate molecule induces the ordering of switch I and switch II to complete the active site of Ras.
Allosteric modulation of Ras positions Q61 for a direct role in catalysis., Buhrman G, Holzapfel G, Fetics S, Mattos C, Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4931-6. Epub 2010 Mar 1. PMID:20194776
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
3K8Y is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
- Buhrman G, Holzapfel G, Fetics S, Mattos C. Allosteric modulation of Ras positions Q61 for a direct role in catalysis. Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):4931-6. Epub 2010 Mar 1. PMID:20194776
Page seeded by OCA on Wed May 12 10:34:56 2010
Categories: Homo sapiens | Buhrman, G. | Holzapfel, G. | Mattos, C. | Acetylation | Cell membrane | Disease mutation | Golgi apparatus | Gtp-binding | Lipoprotein | Membrane | Methylation | Nucleotide-binding | Oncoprotein | Palmitate | Prenylation | Protein-nucleotide complex | Proto-oncogene | S-nitrosylation
