PDBsum entry 5c9c

Transferase/transferase inhibitor

PDB id: 5c9c

Contents

Protein chains

254 a.a.

Ligands

4Z5 ×2

Metals

_CL

Waters ×135

PDB id:

5c9c

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of braf(v600e) in complex with ly3009120 compnd

Structure:

Serine/threonine-protein kinase b-raf. Chain: a, b. Fragment: 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:

2.70Å R-factor: 0.196 R-free: 0.238

Authors:

T.Edwards,J.Abendroth,L.Chun

Key ref:

S.B.Peng et al. (2015). Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell, 28, 384-398. PubMed id: 26343583 DOI: 10.1016/j.ccell.2015.08.002

Date:

26-Jun-15 Release date: 15-Jul-15

Protein chains

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

Seq: 766 a.a.

Struc: 254 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

DOI no: 10.1016/j.ccell.2015.08.002

Cancer Cell 28:384-398 (2015)

PubMed id: 26343583

Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers.

S.B.Peng, J.R.Henry, M.D.Kaufman, W.P.Lu, B.D.Smith, S.Vogeti, T.J.Rutkoski, S.Wise, L.Chun, Y.Zhang, R.D.Van Horn, T.Yin, X.Zhang, V.Yadav, S.H.Chen, X.Gong, X.Ma, Y.Webster, S.Buchanan, I.Mochalkin, L.Huber, L.Kays, G.P.Donoho, J.Walgren, D.McCann, P.Patel, I.Conti, G.D.Plowman, J.J.Starling, D.L.Flynn.

ABSTRACT

LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.