<unk> 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<unk> 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,<unk> forms dimers via hydrogen-bonding and electrostatic interactions of its kinase domains. CR1 Conserved region 1 autoinhibits B-Raf's kinase domain (CR3) so that<unk> 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<unk> membrane docking after Ras-binding. CR2 Conserved Region 2 (CR2) provides a flexible linker that connects CR1 and CR3 and acts as a hinge. CR3 Figure 1: Inactive conformation of<unk> kinase (CR3) domain. P-Loop (orange) hydrophobic interactions with activation loop (gray) residues that stabilize the inactive kinase conformation are shown with sticks. F595 (red) blocks the hydrophobic pocket where the ATP adenine binds (yellow). D576 (orange) is shown as part of the catalytic loop (magenta). Figure modified from PDB id 1UWH. 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. Subregions P-Loop The P-loop of<unk> (residues 464–471) stabilizes the non-transferable phosphate groups of ATP during enzyme ATP-binding. Specifically, S467, F468, and G469 backbone amides hydrogen-bond to the β-phosphate of ATP to anchor the molecule.<unk> functional motifs have been determined by analyzing the homology of PKA analyzed by Hanks and Hunter to the<unk> kinase domain. Nucleotide-Binding Pocket V471, C532, W531, T529, L514, and A481 form a hydrophobic pocket within which the adenine of ATP is anchored through Van der Waals attractions upon ATP binding. Catalytic Loop Residues 574–581 compose a section of the kinase domain responsible for supporting the transfer of the γ-phosphate of ATP to B-Raf's protein substrate. In particular, D576 acts as a proton acceptor to activate the nucleophilic hydroxyl oxygen on substrate serine or threonine residues, allowing the phosphate transfer reaction to occur mediated by base-catalysis. DFG Motif D594, F595, and G596 compose a motif central to B-Raf's function in both its inactive and active state. In the inactive state, F595 occupies the nucleotide-binding pocket, prohibiting ATP from entering and decreasing the likelihood of enzyme catalysis. In the active state, D594 chelates the divalent magnesium cation that stabilizes the β- and γ-phosphate groups of ATP, orienting the γ-phosphate for transfer. Activation Loop Residues 596–600 form strong hydrophobic interactions with the P-loop in the inactive conformation of the kinase, locking the kinase in its inactive state until the activation loop is phosphorylated, destabilizing these interactions with the presence of negative charge. This triggers the shift to the active state of the kinase. Specifically, L597 and V600 of the activation loop interact with G466, F468, and V471 of the P-loop to keep the kinase domain inactive until it is phosphorylated.
BRAF 
KRAS
ABL 
TFM-4AS-1
Kras
P73
HERG
CoWIN