PDBsum entry 6d56

Signaling protein

PDB id: 6d56

Contents

Protein chains

166 a.a.

469 a.a.

Ligands

GNP

FVM

FMT ×6

GOL ×2

Metals

_MG

_NA

Waters ×1144

PDB id:

6d56

Name:

Signaling protein

Title:

Ras:sos:ras in complex with a small molecule activator

Structure:

Gtpase hras. Chain: a. Synonym: h-ras-1,ha-ras,transforming protein p21,c-h-ras,p21ras. Engineered: yes. Mutation: yes. Son of sevenless homolog 1. Chain: b. Synonym: sos-1. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hras, hras1. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: sos1. Expression_system_taxid: 562

Resolution:

1.68Å R-factor: 0.160 R-free: 0.171

Authors:

J.Phan,T.Hodges,S.W.Fesik

Key ref:

T.R.Hodges et al. (2018). Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS. J Med Chem, 61, 8875-8894. PubMed id: 30205005 DOI: 10.1021/acs.jmedchem.8b01108

Date:

19-Apr-18 Release date: 19-Sep-18

Protein chains

P01112  (RASH_HUMAN) -  GTPase HRas from Homo sapiens

Seq: 189 a.a.

Struc: 166 a.a.*

Protein chain

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

Seq: 1333 a.a.

Struc: 469 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

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

GTP + H2O = GDP (Bound ligand (Het Group name = GNP) matches with 81.82% similarity) + phosphate + H(+)

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

reference

DOI no: 10.1021/acs.jmedchem.8b01108

J Med Chem 61:8875-8894 (2018)

PubMed id: 30205005

Discovery and Structure-Based Optimization of Benzimidazole-Derived Activators of SOS1-Mediated Nucleotide Exchange on RAS.

T.R.Hodges, J.R.Abbott, A.J.Little, D.Sarkar, J.M.Salovich, J.E.Howes, D.T.Akan, J.Sai, A.L.Arnold, C.Browning, M.C.Burns, T.Sobolik, Q.Sun, Y.Beesetty, J.A.Coker, D.Scharn, H.Stadtmueller, O.W.Rossanese, J.Phan, A.G.Waterson, D.B.McConnell, S.W.Fesik.

ABSTRACT

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.