PDBsum entry 5cu3

Transferase

PDB id: 5cu3

Contents

Protein chains

325 a.a.

Ligands

ACT ×5

54S ×2

DMS ×2

PO4

Waters ×353

PDB id:

5cu3

Name:

Transferase

Title:

Crystal structure of ck2alpha bound to cam4066

Structure:

Casein kinase ii subunit alpha. Chain: a, b. Fragment: unp residues 2-329. Synonym: ck ii alpha. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csnk2a1, ck2a1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.79Å R-factor: 0.185 R-free: 0.202

Authors:

P.Brear,C.De Fusco,K.H.Georgiou,D.Spring,M.Hyvonen

Key ref:

P.Brear et al. (2016). Specific inhibition of CK2α from an anchor outside the active site. Chem Sci, 7, 6839-6845. PubMed id: 28451126

Date:

24-Jul-15 Release date: 27-Jul-16

Protein chains

P68400  (CSK21_HUMAN) -  Casein kinase II subunit alpha from Homo sapiens

Seq: 391 a.a.

Struc: 325 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein 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⁺

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

reference

Chem Sci 7:6839-6845 (2016)

PubMed id: 28451126

Specific inhibition of CK2α from an anchor outside the active site.

P.Brear, C.De Fusco, K.Hadje Georgiou, N.J.Francis-Newton, C.J.Stubbs, H.F.Sore, A.R.Venkitaraman, C.Abell, D.R.Spring, M.Hyvönen.

ABSTRACT

The development of selective inhibitors of protein kinases is challenging because of the significant conservation of the ATP binding site. Here, we describe a new mechanism by which the protein kinase CK2α can be selectively inhibited using features outside the ATP site. We have identified a new binding site for small molecules on CK2α adjacent to the ATP site and behind the αD loop, termed the αD pocket. An elaborated fragment anchored in this site has been linked with a low affinity fragment binding in the ATP site, creating a novel and selective inhibitor (CAM4066) that binds CK2α with aK_dof 320 nM and shows significantly improved selectivity compared to other CK2α inhibitors. CAM4066 shows target engagement in several cell lines and similar potency to clinical trial candidate CX4945. Our data demonstrate that targeting a poorly conserved, cryptic pocket allows inhibition of CK2αviaa novel mechanism, enabling the development of a new generation of selective CK2α inhibitors.