PDBsum entry 4xv2

Transferase/transferase inhibitor

PDB id: 4xv2

Contents

Protein chains

247 a.a.

Ligands

P06 ×2

Waters ×54

PDB id:

4xv2

Name:

Transferase/transferase inhibitor

Title:

B-raf kinase v600e oncogenic mutant in complex with dabrafenib

Structure:

Serine/threonine-protein kinase b-raf. Chain: a, b. Fragment: unp residues 444-705. 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: escherichia coli. Expression_system_taxid: 562

Resolution:

2.50Å R-factor: 0.213 R-free: 0.244

Authors:

Y.Zhang,C.Zhang

Key ref:

C.Zhang et al. (2015). RAF inhibitors that evade paradoxical MAPK pathway activation. Nature, 526, 583-586. PubMed id: 26466569 DOI: 10.1038/nature14982

Date:

26-Jan-15 Release date: 28-Oct-15

Protein chains

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

Seq: 766 a.a.

Struc: 247 a.a.*

* PDB and UniProt seqs differ at 13 residue positions (black crosses)

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

DOI no: 10.1038/nature14982

Nature 526:583-586 (2015)

PubMed id: 26466569

RAF inhibitors that evade paradoxical MAPK pathway activation.

C.Zhang, W.Spevak, Y.Zhang, E.A.Burton, Y.Ma, G.Habets, J.Zhang, J.Lin, T.Ewing, B.Matusow, G.Tsang, A.Marimuthu, H.Cho, G.Wu, W.Wang, D.Fong, H.Nguyen, S.Shi, P.Womack, M.Nespi, R.Shellooe, H.Carias, B.Powell, E.Light, L.Sanftner, J.Walters, J.Tsai, B.L.West, G.Visor, H.Rezaei, P.S.Lin, K.Nolop, P.N.Ibrahim, P.Hirth, G.Bollag.

ABSTRACT

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.