PDBsum entry 4twn

Transferase

PDB id: 4twn

Contents

Protein chain

276 a.a.

Ligands

B96

Waters ×178

PDB id:

4twn

Name:

Transferase

Title:

Human epha3 kinase domain in complex with birb796

Structure:

Ephrin type-a receptor 3. Chain: a. Fragment: kinase domain (unp residues 609-947). Synonym: eph-like kinase 4,hek4,hek,human embryo kinase,tyrosine- protein kinase tyro4,tyrosine-protein kinase receptor etk1,eph-like tyrosine kinase 1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: epha3, etk, etk1, hek, tyro4. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.71Å R-factor: 0.179 R-free: 0.213

Authors:

J.Dong,A.Caflisch

Key ref:

J.Dong et al. (2015). Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases. Acs Med Chem Lett, 6, 79-83. PubMed id: 25589935 DOI: 10.1021/ml500355x

Date:

01-Jul-14 Release date: 13-May-15

Protein chain

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

Seq: 983 a.a.

Struc: 276 a.a.*

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

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⁺

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

Added reference

DOI no: 10.1021/ml500355x

Acs Med Chem Lett 6:79-83 (2015)

PubMed id: 25589935

Structural Analysis of the Binding of Type I, I1/2, and II Inhibitors to Eph Tyrosine Kinases.

J.Dong, H.Zhao, T.Zhou, D.Spiliotopoulos, C.Rajendran, X.D.Li, D.Huang, A.Caflisch.

ABSTRACT

We have solved the crystal structures of the EphA3 tyrosine kinase in complex with nine small-molecule inhibitors, which represent five different chemotypes and three main binding modes, i.e., types I and I1/2 (DFG in) and type II (DFG out). The three structures with type I1/2 inhibitors show that the higher affinity with respect to type I is due to an additional polar group (hydroxyl or pyrazole ring of indazole) which is fully buried and is involved in the same hydrogen bonds as the (urea or amide) linker of the type II inhibitors. Overall, the type I and type II binding modes belong to the lock-and-key and induced fit mechanism, respectively. In the type II binding, the scaffold in contact with the hinge region influences the position of the Phe765 side chain of the DFG motif and the orientation of the Gly-rich loop. The binding mode of Birb796 in the EphA3 kinase does not involve any hydrogen bond with the hinge region, which is different from the Birb796/p38 MAP kinase complex. Our structural analysis emphasizes the importance of accounting for structural plasticity of the ATP binding site in the design of type II inhibitors of tyrosine kinases.