5xqx
From Proteopedia
Human CDK8-CYCC in complex with compound 4: N-methyl-4-(4-pyridyl)-1H-pyrrole-2-carboxamide
Structural highlights
Function[CDK8_HUMAN] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.[1] [2] [CCNC_HUMAN] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.[3] [4] Publication Abstract from PubMedA fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability. Discovery of potent and selective CDK8 inhibitors through FBDD approach.,Han X, Jiang M, Zhou C, Zhou Z, Xu Z, Wang L, Mayweg AV, Niu R, Jin TG, Yang S Bioorg Med Chem Lett. 2017 Aug 1. pii: S0960-894X(17)30787-4. doi:, 10.1016/j.bmcl.2017.07.080. PMID:28802632[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Xu, Z H | Zhou, Z | Cdk8 | Cyclin c | Mediator complex | Transferase
