PDBsum entry 4lyh

Signaling protein/inhibitor

PDB id: 4lyh

Contents

Protein chains

163 a.a.

Ligands

SO4 ×2

GDP ×3

21F ×2

Waters ×389

PDB id:

4lyh

Name:

Signaling protein/inhibitor

Title:

Crystal structure of small molecule vinylsulfonamide 9 covalently bound to k-ras g12c

Structure:

Gtpase kras. Chain: a, b, c. Fragment: unp residues 1-169. Synonym: k-ras 2, ki-ras, c-k-ras, c-ki-ras, gtpase kras, n- terminally processed. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kras, kras isoform 2b, kras2, rask2. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.37Å R-factor: 0.165 R-free: 0.188

Authors:

J.M.Ostrem,U.Peters,M.L.Sos,J.A.Wells,K.M.Shokat

Key ref:

J.M.Ostrem et al. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503, 548-551. PubMed id: 24256730 DOI: 10.1038/nature12796

Date:

31-Jul-13 Release date: 27-Nov-13

Protein chains

P01116  (RASK_HUMAN) -  GTPase KRas from Homo sapiens

Seq: 189 a.a.

Struc: 163 a.a.*

* PDB and UniProt seqs differ at 10 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.6.5.2 - small monomeric GTPase.
• Reaction: GTP + H2O = GDP + phosphate + H⁺

GTP + H2O = GDP (Bound ligand (Het Group name = GDP) corresponds exactly) + phosphate + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nature12796

Nature 503:548-551 (2013)

PubMed id: 24256730

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.

J.M.Ostrem, U.Peters, M.L.Sos, J.A.Wells, K.M.Shokat.

ABSTRACT

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.