7jv1 | pdb_00007jv1

Crystal Structure of KSR1:MEK1 in complex with AMP-PNP, and allosteric MEK inhibitor APS-9-95-1

spinqualitylabelsall models 7jv1, resolution 3.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7jv1 is a 2 chain structure with sequence from Homo sapiens and Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.62Å Ligands: ANP, MG, VKG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KSR1_HUMAN Scaffolding protein that is part of a multiprotein signaling complex. Promotes phosphorylation of Raf family members and activation of downstream MAP kinases. Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP. Does not have kinase activity by itself.[UniProtKB:Q61097] Publication Abstract from PubMed The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology(1), and more recently in immunotherapy(2,3) and aging(4). However, many MEK inhibitors (MEKi) are limited due to on-target toxicities(5-7) and drug resistance(8-10). Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEKi, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including drug residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these subcomplexes. Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. Together, our results reveal the plasticity of an interface pocket within MEK subcomplexes that has implications for the design of next-generation drugs targeting the RAS pathway. Structural basis for the action of the drug trametinib at KSR-bound MEK.,Khan ZM, Real AM, Marsiglia WM, Chow A, Duffy ME, Yerabolu JR, Scopton AP, Dar AC Nature. 2020 Sep 14. pii: 10.1038/s41586-020-2760-4. doi:, 10.1038/s41586-020-2760-4. PMID:32927473 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Mitogen-activated protein kinase kinase 3D structures

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