Based on these insights we created trametiglue, which limits adaptive resistance to MEKi through enhanced interfacial binding. 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. Through complexation, KSR remodels the prototypical MEKi allosteric pocket thereby impacting binding and kinetics, including drug residence time. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. 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. 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. However, many MEK inhibitors (MEKi) are limited due to on-target toxicities5-7 and drug resistance8-10.
PROTEIN SCAFFOLD PDF DRIVERS
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 oncology1, and more recently in immunotherapy2,3 and aging4. Please refer to the text for further details. (4) and (5) Di®erent e®ector proteins like MEK2, ERK, RhoA are controlled in di®erent ways by the BCH domain proteins BPGAP-1, p50RhoGAP, BNIP-2 and BNIP-S, and their partners.
BPGAP1 activates Ras-ERK signalling to promote neurite outgrowth. (3) BNIP-H plays an important role in neurite outgrowth and neuronal di®erentiation through its various interaction with kinesin motor protein KIF5 to transport glutaminase KGA to produce glutamate, or to transport ACL and ChAT, two enzymes that produce the neurotransmitter acetylcholine. (1) and (2) BNIP-2 plays an important role in muscle di®erentiation and a®ects cellular di®erentiation through the formation of protrusion and interaction with e®ectors like Cdo and Cdc42 etc. BCH domain-containing proteins like BNIP-2, BPGAP-1, p50Rho-GAP, BNIP-H, BNIP-S have been widely studied in our lab and their diverse e®ectors and physiological roles have been established. Future studies of scaffold proteins should give us an in-depth knowledge of how cell signaling works in normal and pathological conditions and would offer avenues to disrupt harmful cellular pathways to circumvent diseases.ĭynamic role of the BCH domain-containing protein. Their versatility and functions in human diseases make them attractive drug targets, several of which have been investigated in clinical trials. Here, we discuss the role of several scaffold proteins which are implicated in important signaling pathways that play important roles in cardiac diseases, metabolic diseases, neurological disorders, and cancer. Years of research in this¯eld have revealed the versatility of this class of protein and the important role it plays in maintaining the normal functions of the human body. They control signal transduction and assist the localization of pathway components (organized in complexes) to definite regions of the cell such as the endosomes, plasma membrane, the cytoplasm, mitochondria, Golgi, and the nucleus. Though scaffolds are not stringently de¯ned in meaning, they are known to interact with numerous components of a signaling pathway, binding and bridging them into distinct and functional complexes. Scaffold proteins are critical regulators of important cell signaling pathways.
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