8VM2

Crystal Structure of NRAS Q61K bound to GTP

Summary for 8VM2

• Entry DOI: 10.2210/pdb8vm2/pdb
• Descriptor: GTPase NRas, GUANOSINE-5'-TRIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: nras, oncogenic mutation, ras superfamily small gtpases, hydrolase, hydrolase-oncoprotein complex, hydrolase/oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 68042.84

Authors

Gebregiworgis, T.,Chan, J.Y.L.,Kuntz, D.A.,Prive, G.G.,Marshall, C.B.,Ikura, M. (deposition date: 2024-01-12, release date: 2024-05-01)

Primary citation

Gebregiworgis, T.,Chan, J.Y.,Kuntz, D.A.,Prive, G.G.,Marshall, C.B.,Ikura, M.
Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II.
Eur J Cell Biol, 103:151414-151414, 2024

PubMed Abstract: The RAS isoforms (KRAS, HRAS and NRAS) have distinct cancer type-specific profiles. NRAS mutations are the second most prevalent RAS mutations in skin and hematological malignancies. Although RAS proteins were considered undruggable for decades, isoform and mutation-specific investigations have produced successful RAS inhibitors that are either specific to certain mutants, isoforms (pan-KRAS) or target all RAS proteins (pan-RAS). While extensive structural and biochemical investigations have focused mainly on K- and H-RAS mutations, NRAS mutations have received less attention, and the most prevalent NRAS mutations in human cancers, Q61K and Q61R, are rare in K- and H-RAS. This manuscript presents a crystal structure of the NRAS Q61K mutant in the GTP-bound form. Our structure reveals a previously unseen pocket near switch II induced by the binding of a ligand to the active form of the protein. This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.

PubMed: 38640594
DOI: 10.1016/j.ejcb.2024.151414

Experimental method

X-RAY DIFFRACTION (1.74 Å)