PDBsum entry 4g9r

Transferase/transferase inhibitor

PDB id: 4g9r

Contents

Protein chains

262 a.a.

Ligands

B1E ×2

PDB id:

4g9r

Name:

Transferase/transferase inhibitor

Title:

B-raf v600e kinase domain bound to a type ii dihydroquinazoline inhibitor

Structure:

Serine/threonine-protein kinase b-raf. Chain: a, b. Fragment: kinase domain (unp residues 432-726). Synonym: proto-oncogene b-raf, p94, v-raf murine sarcoma viral oncogene homolog b1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: braf, braf1, rafb1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.

Resolution:

3.20Å R-factor: 0.229 R-free: 0.277

Authors:

W.C.Voegtli,H.L.Sturgis

Key ref:

S.Wenglowsky et al. (2012). Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: rational design and kinase selectivity profile of cell potent type II inhibitors. Bioorg Med Chem Lett, 22, 6237-6241. PubMed id: 22954737

Date:

24-Jul-12 Release date: 14-Nov-12

Protein chains

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

Seq: 766 a.a.

Struc: 262 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

Bioorg Med Chem Lett 22:6237-6241 (2012)

PubMed id: 22954737

Pyrazolopyridine inhibitors of B-Raf(V600E). Part 4: rational design and kinase selectivity profile of cell potent type II inhibitors.

S.Wenglowsky, D.Moreno, E.R.Laird, S.L.Gloor, L.Ren, T.Risom, J.Rudolph, H.L.Sturgis, W.C.Voegtli.

ABSTRACT

Cell potent inhibitors of B-Raf(V600E) that bind to the kinase in the DFG-out conformation are reported. These compounds utilize the hinge-binding group and lipophilic linker from a previously disclosed series of B-Raf(V600E) inhibitors that bind to the kinase in an atypical DFG-in, αC-helix-out conformation. This new series demonstrates that DFG-out kinase inhibitors can be rationally designed from related inhibitors which utilize an unconventional binding mode. Kinase selectivity profiles are compared. The pattern of kinase selectivity was found to be determined by the feature of the inhibitor which extends into the back pocket of the kinase and leads to the kinase conformation, rather than by the hinge-binding group or other minor modifications.