5mjb

Kinase domain of human EphB1, G703C mutant, covalently bound to a quinazoline-based inhibitor

spinqualitylabelsall models 5mjb, resolution 2.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mjb is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.23Å Ligands: 7O3, PTR, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EPHB1_HUMAN Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively. Publication Abstract from PubMed Although a previously developed bump-hole approach has proven powerful in generating specific inhibitors for mapping functions of protein kinases, its application is limited by the intolerance of the large-to-small mutation by certain kinases and the inability to control two kinases separately in the same cells. Herein, we describe the development of an alternative chemical-genetic approach to overcome these limitations. Our approach features the use of an engineered cysteine residue at a particular position as a reactive feature to sensitize a kinase of interest to selective covalent blockade by electrophilic inhibitors and is thus termed the Ele-Cys approach. We successfully applied the Ele-Cys approach to identify selective covalent inhibitors of a receptor tyrosine kinase EphB1 and solved cocrystal structures to determine the mode of covalent binding. Importantly, the Ele-Cys and bump-hole approaches afforded orthogonal inhibition of two distinct kinases in the cell, opening the door to their combined use in the study of multikinase signaling pathways. A Chemical-Genetic Approach to Generate Selective Covalent Inhibitors of Protein Kinases.,Kung A, Schimpl M, Ekanayake A, Chen YC, Overman R, Zhang C ACS Chem Biol. 2017 May 8. doi: 10.1021/acschembio.6b01083. PMID:28459525 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ephrin receptor 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA