PDBsum entry 4g2f

Transferase/transferase inhibitor

PDB id: 4g2f

Contents

Protein chain

275 a.a.

Ligands

C07

Waters ×225

PDB id:

4g2f

Name:

Transferase/transferase inhibitor

Title:

Human epha3 kinase domain in complex with compound 7

Structure:

Eph receptor a3. Chain: a. Fragment: kinase domain, unp residues 606-947. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: epha3. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.70Å R-factor: 0.180 R-free: 0.209

Authors:

J.Dong,A.Caflisch

Key ref:

H.Zhao et al. (2012). Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics. Acs Med Chem Lett, 3, 834-838. PubMed id: 24900387 DOI: 10.1021/ml3001984

Date:

12-Jul-12 Release date: 24-Oct-12

Protein chain

P29320  (EPHA3_HUMAN) -  Ephrin type-A receptor 3 from Homo sapiens

Seq: 983 a.a.

Struc: 275 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = C07) matches with 41.67% similarity) + ADP + H(+)

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

Added reference

DOI no: 10.1021/ml3001984

Acs Med Chem Lett 3:834-838 (2012)

PubMed id: 24900387

Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics.

H.Zhao, J.Dong, K.Lafleur, C.Nevado, A.Caflisch.

ABSTRACT

We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 μM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 Å resolution.