PDBsum entry 3q4c

Transferase/transferase inhibitor

PDB id: 3q4c

Contents

Protein chains

264 a.a. *

Ligands

RSW

* Residue conservation analysis

PDB id:

3q4c

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of wild type braf kinase domain in complex with organometallic inhibitor cns292

Structure:

Serine/threonine-protein kinase b-raf. Chain: a, b. Synonym: proto-oncogene b-raf, p94, v-raf murine sarcoma viral oncogene homolog b1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: braf, braf1, rafb1. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469.

Resolution:

3.20Å R-factor: 0.232 R-free: 0.280

Authors:

P.Xie,C.Streu,J.Qin,H.Pregman,N.Pagano,E.Meggers,R.Marmorstein

Key ref:

P.Xie et al. (2009). The crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase. Biochemistry, 48, 5187-5198. PubMed id: 19371126

Date:

23-Dec-10 Release date: 02-Mar-11

Protein chains

P15056  (BRAF_HUMAN) -  Serine/threonine-protein kinase B-raf from Homo sapiens

Seq: 766 a.a.

Struc: 264 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

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

reference

Biochemistry 48:5187-5198 (2009)

PubMed id: 19371126

The crystal structure of BRAF in complex with an organoruthenium inhibitor reveals a mechanism for inhibition of an active form of BRAF kinase.

P.Xie, C.Streu, J.Qin, H.Bregman, N.Pagano, E.Meggers, R.Marmorstein.

ABSTRACT

Substitution mutations in the BRAF serine/threonine kinase are found in a variety of human cancers. Such mutations occur in approximately 70% of human malignant melanomas, and a single hyperactivating V600E mutation is found in the activation segment of the kinase domain and accounts for more than 90% of these mutations. Given this correlation, the molecular mechanism for BRAF regulation as well as oncogenic activation has attracted considerable interest, and activated forms of BRAF, such as BRAF(V600E), have become attractive targets for small molecule inhibition. Here we report on the identification and subsequent optimization of a potent BRAF inhibitor, CS292, based on an organometallic kinase inhibitor scaffold. A cocrystal structure of CS292 in complex with the BRAF kinase domain reveals that CS292 binds to the ATP binding pocket of the kinase and is an ATP competitive inhibitor. The structure of the kinase-inhibitor complex also demonstrates that CS292 binds to BRAF in an active conformation and suggests a mechanism for regulation of BRAF by phosphorylation and BRAF(V600E) oncogene-induced activation. The structure of CS292 bound to the active form of the BRAF kinase also provides a novel scaffold for the design of BRAF(V600E) oncogene selective BRAF inhibitors for therapeutic application.