PDBsum entry 4bi0

Transferase

PDB id: 4bi0

Contents

Protein chain

254 a.a.

Ligands

7PE ×2

Z0W

EDO

Waters ×15

PDB id:

4bi0

Name:

Transferase

Title:

Scaffold focused virtual screening: prospective application to the discovery of ttk inhibitor

Structure:

Dual specificity protein kinase ttk. Chain: a. Fragment: kinase domain, residues 518-807. Synonym: phosphotyrosine picked threonine-protein kinase, pyt, monopolar spindle kinase 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: ai

Resolution:

2.84Å R-factor: 0.186 R-free: 0.224

Authors:

S.R.Langdon,I.M.Westwood,R.L.M.Van Montfort,N.Brown,J.Blagg

Key ref:

S.R.Langdon et al. (2013). Scaffold-focused virtual screening: prospective application to the discovery of TTK inhibitors. J Chem Inf Model, 53, 1100-1112. PubMed id: 23672464 DOI: 10.1021/ci400100c

Date:

09-Apr-13 Release date: 22-May-13

Protein chain

P33981  (TTK_HUMAN) -  Dual specificity protein kinase TTK from Homo sapiens

Seq: 857 a.a.

Struc: 254 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.12.1 - dual-specificity 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⁺
  3. L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] (Bound ligand (Het Group name = Z0W) matches with 42.86% similarity) + ADP + H(+)

L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] (Bound ligand (Het Group name = Z0W) matches with 42.86% similarity) + ADP + H(+)

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = Z0W) matches with 42.86% similarity) + ADP + H(+)

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

reference

DOI no: 10.1021/ci400100c

J Chem Inf Model 53:1100-1112 (2013)

PubMed id: 23672464

Scaffold-focused virtual screening: prospective application to the discovery of TTK inhibitors.

S.R.Langdon, I.M.Westwood, R.L.van Montfort, N.Brown, J.Blagg.

ABSTRACT

We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein-ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design.