BRAF inhibitor

1UWH, 1UWJ, 2FB8, 2L05, 3C4C, 3D4Q, 3IDP, 3II5, 3NY5, 3OG7, 3PPJ, 3PPK, 3PRF, 3PRI, 3PSB, 3PSD, 3Q4C, 3Q96, 3SKC, 3TV4, 3TV6, 4DBN, 4E26, 4E4X, 4EHE, 4EHG, 4FC0, 4FK3, 4G9C, 4G9R, 4H58, 4JVG, 4KSP, 4KSQ, 4MBJ, 4MNE, 4MNF, 4PP7, 4WO5, 5C9C, 5CT7, 4XV2, 4XV1, 4XV9, 4XV3, 4R5Y, 5CSW, 5CSX, 4YHT, 5J2R, 5FD2, 5HIE, 5HID, 5HI2, 4CQE, 5J18673109880ENSG00000157764ENSMUSG00000002413P15056P28028NM_004333NM_001354609NM_139294NP_004324NP_001341538NP_647455BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.1uwh: THE COMPLEX OF WILD TYPE B-RAF AND BAY4390061uwj: THE COMPLEX OF MUTANT V599E B-RAF AND BAY4390062fb8: Structure of the B-Raf kinase domain bound to SB-590885 BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf. The B-Raf protein is involved in sending signals inside cells which are involved in directing cell growth. In 2002, it was shown to be faulty (mutated) in some human cancers. Certain other inherited BRAF mutations cause birth defects. Drugs that treat cancers driven by BRAF mutations have been developed. Two of these drugs, vemurafenib and dabrafenib are approved by FDA for treatment of late-stage melanoma. Vemurafenib was the first drug to come out of fragment-based drug discovery. B-Raf is a member of the Raf kinase family of growth signal transduction protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. B-Raf is a 766-amino acid, regulated signal transduction serine/threonine-specific protein kinase. Broadly speaking, it is composed of three conserved domains characteristic of the Raf kinase family: conserved region 1 (CR1), a Ras-GTP-binding self-regulatory domain, conserved region 2 (CR2), a serine-rich hinge region, and conserved region 3 (CR3), a catalytic protein kinase domain that phosphorylates a consensus sequence on protein substrates. In its active conformation, B-Raf forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains. Conserved region 1 autoinhibits B-Raf's kinase domain (CR3) so that B-Raf signaling is regulated rather than constitutive. Residues 155–227 make up the Ras-binding domain (RBD), which binds to Ras-GTP's effector domain to release CR1 and halt kinase inhibition. Residues 234–280 comprise a phorbol ester/DAG-binding zinc finger motif that participates in B-Raf membrane docking after Ras-binding. Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge. Conserved Region 3 (CR3), residues 457–717, makes up B-Raf's enzymatic kinase domain. This largely conserved structure is bi-lobal, connected by a short hinge region. The smaller N-lobe (residues 457–530) is primarily responsible for ATP binding while the larger C-lobe (residues 535–717) binds substrate proteins. The active site is the cleft between the two lobes, and the catalytic Asp576 residue is located on the C-lobe, facing the inside of this cleft.