5WDP

H-Ras mutant L120A bound to GMP-PNP at 277K

Summary for 5WDP

• Entry DOI: 10.2210/pdb5wdp/pdb
• Descriptor: GTPase HRas, CALCIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• Functional Keywords: small g-protein, gtpase, oncoprotein, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 19484.07

Authors

Cofsky, J.C.,Bandaru, P.,Gee, C.L.,Kuriyan, J. (deposition date: 2017-07-05, release date: 2017-07-19, Last modification date: 2023-10-04)

Primary citation

Bandaru, P.,Shah, N.H.,Bhattacharyya, M.,Barton, J.P.,Kondo, Y.,Cofsky, J.C.,Gee, C.L.,Chakraborty, A.K.,Kortemme, T.,Ranganathan, R.,Kuriyan, J.
Deconstruction of the Ras switching cycle through saturation mutagenesis.
Elife, 6:-, 2017

PubMed Abstract: Ras proteins are highly conserved signaling molecules that exhibit regulated, nucleotide-dependent switching between active and inactive states. The high conservation of Ras requires mechanistic explanation, especially given the general mutational tolerance of proteins. Here, we use deep mutational scanning, biochemical analysis and molecular simulations to understand constraints on Ras sequence. Ras exhibits global sensitivity to mutation when regulated by a GTPase activating protein and a nucleotide exchange factor. Removing the regulators shifts the distribution of mutational effects to be largely neutral, and reveals hotspots of activating mutations in residues that restrain Ras dynamics and promote the inactive state. Evolutionary analysis, combined with structural and mutational data, argue that Ras has co-evolved with its regulators in the vertebrate lineage. Overall, our results show that sequence conservation in Ras depends strongly on the biochemical network in which it operates, providing a framework for understanding the origin of global selection pressures on proteins.

PubMed: 28686159
DOI: 10.7554/eLife.27810

Experimental method

X-RAY DIFFRACTION (1.35 Å)