PDBsum entry 3pj3

Transferase/inhibitor

PDB id: 3pj3

Contents

Protein chain

240 a.a.

Ligands

04L

Waters ×96

PDB id:

3pj3

Name:

Transferase/inhibitor

Title:

Crystal structure of btk kinase domain complexed with 2-methyl-5-[(e)- (3-phenyl-acryloyl)amino]-n-(2-phenyl-3h-imidazo[4,5-b]pyridin-6-yl)- benzamide

Structure:

Tyrosine-protein kinase btk. Chain: a. Fragment: unp residues 387-659. Synonym: agammaglobulinaemia tyrosine kinase, atk, b-cell progenitor kinase, bpk, bruton tyrosine kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: agmx1, atk, bpk, btk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.85Å R-factor: 0.234 R-free: 0.254

Authors:

A.Kuglstatter,A.Wong

Key ref:

A.Kuglstatter et al. (2011). Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures. Protein Sci, 20, 428-436. PubMed id: 21280133

Date:

08-Nov-10 Release date: 12-Jan-11

Protein chain

Q06187  (BTK_HUMAN) -  Tyrosine-protein kinase BTK from Homo sapiens

Seq: 659 a.a.

Struc: 240 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific 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

Protein Sci 20:428-436 (2011)

PubMed id: 21280133

Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures.

A.Kuglstatter, A.Wong, S.Tsing, S.W.Lee, Y.Lou, A.G.Villaseñor, J.M.Bradshaw, D.Shaw, J.W.Barnett, M.F.Browner.

ABSTRACT

Bruton's tyrosine kinase (BTK) plays a key role in B cell receptor signaling and is considered a promising drug target for lymphoma and inflammatory diseases. We have determined the X-ray crystal structures of BTK kinase domain in complex with six inhibitors from distinct chemical classes. Five different BTK protein conformations are stabilized by the bound inhibitors, providing insights into the structural flexibility of the Gly-rich loop, helix C, the DFG sequence, and activation loop. The conformational changes occur independent of activation loop phosphorylation and do not correlate with the structurally unchanged WEI motif in the Src homology 2-kinase domain linker. Two novel activation loop conformations and an atypical DFG conformation are observed representing unique inactive states of BTK. Two regions within the activation loop are shown to structurally transform between 3(10)- and α-helices, one of which collapses into the adenosine-5'-triphosphate binding pocket. The first crystal structure of a Tec kinase family member in the pharmacologically important DFG-out conformation and bound to a type II kinase inhibitor is described. The different protein conformations observed provide insights into the structural flexibility of BTK, the molecular basis of its regulation, and the structure-based design of specific inhibitors.