4cxa

Crystal structure of the human CDK12-cyclin K complex bound to AMPPNPCrystal structure of the human CDK12-cyclin K complex bound to AMPPNP

Structural highlights 4cxa is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NonStd Res: Activity: Cyclin-dependent kinase, with EC number 2.7.11.22 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [CDK12_HUMAN] Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2. Function [CDK12_HUMAN] Cyclin-dependent kinase which displays CTD kinase activity and is required for RNA splicing. Has CTD kinase activity by hyperphosphorylating the C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit RPB1, thereby acting as a key regulator of transcription elongation. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogn inhibitors. [CCNK_HUMAN] May play a role in transcriptional regulation. In vitro, is associated with a kinase activity toward both RNA polymerase II C-terminal domain and CDK2 (CAK). Publication Abstract from PubMed Cyclin-dependent kinase 12 (CDK12) promotes transcriptional elongation by phosphorylation of the RNA polymerase II C-terminal domain (CTD). Structure-function studies show that this activity is dependent on a C-terminal kinase extension, as well as the binding of cyclin K (CycK). To better define these interactions we determined the crystal structure of the human CDK12/CycK complex with and without the kinase extension in the presence of AMP-PNP. The structures revealed novel features for a CDK, including a large beta4-beta5 loop insertion that contributes to the N-lobe interaction with the cyclin. We also observed two different conformations of the C-terminal kinase extension that effectively open and close the ATP pocket. Most notably, bound AMP-PNP was only observed when trapped in the closed state. Truncation of this C-terminal structure also diminished AMP-PNP binding, as well as the catalytic activity of the CDK12/CycK complex. Further kinetic measurements showed that the full length CDK12/CycK complex was significantly more active than the two crystallised constructs suggesting a critical role for additional domains. Overall, these results demonstrate the intrinsic flexibility of the C-terminal extension in CDK12 and highlight its importance for both ATP binding and kinase activity. Structures of the CDK12/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding.,Dixon-Clarke SE, Elkins JM, Cheng SW, Morin GB, Bullock AN Sci Rep. 2015 Nov 24;5:17122. doi: 10.1038/srep17122. PMID:26597175 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cyclin Cyclin-dependent kinase

spinqualitylabelsall models 4cxa, resolution 3.15Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image