6op9

HER3 pseudokinase domain bound to bosutinib

spinqualitylabelsall models 6op9, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6op9 is a 1 chain structure with sequence from Homo sapiens. This structure supersedes the now removed PDB entry 4otw. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.501Å Ligands: DB8 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ERBB3_HUMAN Defects in ERBB3 are the cause of lethal congenital contracture syndrome type 2 (LCCS2) [MIM:607598; also called Israeli Bedouin multiple contracture syndrome type A. LCCS2 is an autosomal recessive neurogenic form of a neonatally lethal arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. The LCCS2 syndrome is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder. The phenotype suggests a spinal cord neuropathic etiology. Function ERBB3_HUMAN Binds and is activated by neuregulins and NTAK. Publication Abstract from PubMed Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers.,Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, Littlefield P, Steri V, Oeffinger J, Sampang M, Shan Y, Shaw DE, Jura N, Moasser MM Cell Rep. 2022 Feb 1;38(5):110291. doi: 10.1016/j.celrep.2021.110291. PMID:35108525 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA