5kkr | pdb_00005kkr

KSR2:MEK1 Complex Bound to the Small Molecule APS-2-79

spinqualitylabelsall models 5kkr, resolution 3.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5kkr is a 2 chain structure with sequence from European rabbit and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 6U7 Gene: KSR2 (HUMAN), MAP2K1, MEK1, PRKMK1 (European rabbit) Activity: Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.,Dhawan NS, Scopton AP, Dar AC Nature. 2016 Aug 24;537(7618):112-116. doi: 10.1038/nature19327. PMID:27556948 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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