PDBsum entry 5cu0

Transferase

PDB id: 5cu0

Contents

Protein chains

327 a.a.

Ligands

54R ×4

54G ×2

ACT

Waters ×180

PDB id:

5cu0

Name:

Transferase

Title:

Crystal structure of ck2alpha with 2-hydroxy-5-methylbenzoic acid and n-(3-(3-chloro-4-(phenyl)benzylamino)propyl)acetamide bound

Structure:

Casein kinase ii subunit alpha. Chain: a, b. Fragment: residues 2-329 and n-terminal extension gsmdiefdddadddgsgsgsgsgs. Synonym: ck ii alpha. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csnk2a1, ck2a1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.18Å R-factor: 0.206 R-free: 0.236

Authors:

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

Key ref:

C.De Fusco et al. (2017). A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066. Bioorg Med Chem, 25, 3471-3482. PubMed id: 28495381

Date:

24-Jul-15 Release date: 30-Nov-16

Protein chains

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

Seq: 391 a.a.

Struc: 327 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

Bioorg Med Chem 25:3471-3482 (2017)

PubMed id: 28495381

A fragment-based approach leading to the discovery of a novel binding site and the selective CK2 inhibitor CAM4066.

C.De Fusco, P.Brear, J.Iegre, K.H.Georgiou, H.F.Sore, M.Hyvönen, D.R.Spring.

ABSTRACT

Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool. The work described herein shows potential for the development of a novel class of CK2 inhibitors.