PDBsum entry 5acb

Transferase

PDB id: 5acb

Contents

Protein chains

237 a.a.

325 a.a.

Ligands

5I1 ×2

PDB id:

5acb

Name:

Transferase

Title:

Crystal structure of the human cdk12-cyclink complex

Structure:

Cyclin-k. Chain: a, b. Synonym: ccnk. Engineered: yes. Cyclin-dependent kinase 12. Chain: c, d. Synonym: cdc2-related kinase, arginine/serine-rich, crkrs, cell division cycle 2-related protein kinase 7, cdc2-related protein kinase 7, cell division protein kinase 12, hcdk12.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.70Å R-factor: 0.223 R-free: 0.262

Authors:

S.E.Dixon Clarke,J.M.Elkins,A.C.W.Pike,A.Mackenzie,S.Goubin,C.Strain- Damerell,P.Mahajan,C.Tallant,R.Chalk,H.Wiggers,J.Kopec, F.Fitzpatrick,N.Burgess-Brown,E.P.Carpenter,F.Von Delft, C.H.Arrowsmith,A.M.Edwards,C.Bountra,A.Bullock

Key ref:

T.Zhang et al. (2016). Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol, 12, 876-884. PubMed id: 27571479 DOI: 10.1038/nchembio.2166

Date:

14-Aug-15 Release date: 15-Jun-16

Protein chains

O75909  (CCNK_HUMAN) -  Cyclin-K from Homo sapiens

Seq: 580 a.a.

Struc: 237 a.a.

Protein chains

Q9NYV4  (CDK12_HUMAN) -  Cyclin-dependent kinase 12 from Homo sapiens

Seq: 1490 a.a.

Struc: 325 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: Chains C, D: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 2: Chains C, D: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nchembio.2166

Nat Chem Biol 12:876-884 (2016)

PubMed id: 27571479

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.

T.Zhang, N.Kwiatkowski, C.M.Olson, S.E.Dixon-Clarke, B.J.Abraham, A.K.Greifenberg, S.B.Ficarro, J.M.Elkins, Y.Liang, N.M.Hannett, T.Manz, M.Hao, B.Bartkowiak, A.L.Greenleaf, J.A.Marto, M.Geyer, A.N.Bullock, R.A.Young, N.S.Gray.

ABSTRACT

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.