PDBsum entry 6epm

Signaling protein

PDB id: 6epm

Contents

Protein chains

169 a.a.

462 a.a.

Ligands

GOL

BQ5

Waters ×230

PDB id:

6epm

Name:

Signaling protein

Title:

Ras guanine nucleotide exchange factor sos1 (rem-cdc25) in complex with kras(g12c) and fragment screening hit f1

Structure:

Gtpase kras. Chain: r. Synonym: k-ras 2,ki-ras,c-k-ras,c-ki-ras. Engineered: yes. Mutation: yes. Other_details: n-terminal gly (position -1 compared to uniprot entry) is a cloning artifact. Son of sevenless homolog 1. Chain: s.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kras, kras2, rask2. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: sos1. Expression_system_taxid: 562

Resolution:

2.50Å R-factor: 0.181 R-free: 0.211

Authors:

R.C.Hillig,D.Moosmayer,A.Hilpmann,B.Bader,J.Schroeder,L.Wortmann, B.Sautier,J.Kahmann,D.Wegener,H.Briem,K.Petersen,V.Badock

Key ref:

R.C.Hillig et al. (2019). Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci U S A, 116, 2551-2560. PubMed id: 30683722 DOI: 10.1073/pnas.1812963116

Date:

12-Oct-17 Release date: 06-Feb-19

Protein chain

P01116  (RASK_HUMAN) -  GTPase KRas from Homo sapiens

Seq: 189 a.a.

Struc: 169 a.a.*

Protein chain

Q07889  (SOS1_HUMAN) -  Son of sevenless homolog 1 from Homo sapiens

Seq: 1333 a.a.

Struc: 462 a.a.

* PDB and UniProt seqs differ at 11 residue positions (black crosses)

Enzyme reactions

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

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

reference

DOI no: 10.1073/pnas.1812963116

Proc Natl Acad Sci U S A 116:2551-2560 (2019)

PubMed id: 30683722

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.

R.C.Hillig, B.Sautier, J.Schroeder, D.Moosmayer, A.Hilpmann, C.M.Stegmann, N.D.Werbeck, H.Briem, U.Boemer, J.Weiske, V.Badock, J.Mastouri, K.Petersen, G.Siemeister, J.D.Kahmann, D.Wegener, N.Böhnke, K.Eis, K.Graham, L.Wortmann, F.von Nussbaum, B.Bader.

ABSTRACT

Since the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS^G12C-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC₅₀ of 21 nM and is a valuable chemical probe for future investigations.