3RRZ

H-Ras in 70% glycerol: one of 10 in MSCS set

Summary for 3RRZ

• Entry DOI: 10.2210/pdb3rrz/pdb
• Related: 3RRY 3RS0 3RS2 3RS3 3RS4 3RS5 3RS7 3RSL 3RSO
• Descriptor: GTPase HRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, GLYCEROL, ... (6 entities in total)
• Functional Keywords: gtp-binding, nucleotide binding, signaling protein
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane. Isoform 2: Nucleus: P01112
• Total number of polymer chains: 1
• Total formula weight: 20262.90

Authors

Mattos, C.,Buhrman, G.,Kearney, B. (deposition date: 2011-05-02, release date: 2011-09-21, Last modification date: 2024-02-28)

Primary citation

Buhrman, G.,O Connor, C.,Zerbe, B.,Kearney, B.M.,Napoleon, R.,Kovrigina, E.A.,Vajda, S.,Kozakov, D.,Kovrigin, E.L.,Mattos, C.
Analysis of Binding Site Hot Spots on the Surface of Ras GTPase.
J.Mol.Biol., 413:773-789, 2011

PubMed Abstract: We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the "off" and "on" allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target.

PubMed: 21945529
DOI: 10.1016/j.jmb.2011.09.011

Experimental method

X-RAY DIFFRACTION (1.6 Å)