PDBsum entry 3fzs

Transferase

PDB id: 3fzs

Contents

Protein chain

254 a.a. *

Ligands

B96

Waters ×261

* Residue conservation analysis

PDB id:

3fzs

Name:

Transferase

Title:

Crystal structure of pyk2 complexed with birb796

Structure:

Protein tyrosine kinase 2 beta. Chain: a. Fragment: unp residues 416-692, protein kinase domain. Synonym: focal adhesion kinase 2, fadk 2, proline-rich tyrosine kinase 2, cell adhesion kinase beta, cak beta, calcium-dependent tyrosine kinase, cadtk, related adhesion focal tyrosine kinase, raftk. Ec: 2.7.10.2

Source:

Homo sapiens. Human. Organism_taxid: 9606

Resolution:

1.75Å R-factor: 0.192 R-free: 0.224

Authors:

S.Han

Key ref:

S.Han et al. (2009). Structural Characterization of Proline-rich Tyrosine Kinase 2 (PYK2) Reveals a Unique (DFG-out) Conformation and Enables Inhibitor Design. J Biol Chem, 284, 13193-13201. PubMed id: 19244237 DOI: 10.1074/jbc.M809038200

Date:

26-Jan-09 Release date: 31-Mar-09

Protein chain

Q14289  (FAK2_HUMAN) -  Protein-tyrosine kinase 2-beta from Homo sapiens

Seq: 1009 a.a.

Struc: 254 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

DOI no: 10.1074/jbc.M809038200

J Biol Chem 284:13193-13201 (2009)

PubMed id: 19244237

Structural Characterization of Proline-rich Tyrosine Kinase 2 (PYK2) Reveals a Unique (DFG-out) Conformation and Enables Inhibitor Design.

S.Han, A.Mistry, J.S.Chang, D.Cunningham, M.Griffor, P.C.Bonnette, H.Wang, B.A.Chrunyk, G.E.Aspnes, D.P.Walker, A.D.Brosius, L.Buckbinder.

ABSTRACT

Proline-rich tyrosine kinase 2 (PYK2) is a cytoplasmic, non-receptor tyrosine kinase implicated in multiple signaling pathways. It is a negative regulator of osteogenesis and considered a viable drug target for osteoporosis treatment. The high-resolution structures of the human PYK2 kinase domain with different inhibitor complexes establish the conventional bilobal kinase architecture and show the conformational variability of the DFG loop. The basis for the lack of selectivity for the classical kinase inhibitor, PF-431396, within the FAK family is explained by our structural analyses. Importantly, the novel DFG-out conformation with two diarylurea inhibitors (BIRB796, PF-4618433) reveals a distinct subclass of non-receptor tyrosine kinases identifiable by the gatekeeper Met-502 and the unique hinge loop conformation of Leu-504. This is the first example of a leucine residue in the hinge loop that blocks the ATP binding site in the DFG-out conformation. Our structural, biophysical, and pharmacological studies suggest that the unique features of the DFG motif, including Leu-504 hinge-loop variability, can be exploited for the development of selective protein kinase inhibitors.

Selected figure(s)

Figure 2.
A, molecular surface of the PYK2 in the active site region in complex with ATPγS (magenta). Critical side chains are labeled (ball and stick representation) with hydrogen bonds (dashed lines). B, active site of PYK2 bound to PF-431396 (magenta). Hydrophobic residues interacting with the sulfonamide group are shown in yellow.

Figure 6.
DFG-out conformation in PYK2. A, conformational change for the DFG motif upon binding of BIRB796. DFG-in motif in Apo structure is shown in purple and the DFG-out conformation in green. B, superposition of the structures of the PYK2: BIRB796 complex (green) from p38: BIRB796 complex (orange) showing significant differences represented by arrows. C, stereoview showing the DFG-out binding sites of Imatinib from Abl (yellow), Sorafenib from B-RAF (gray), and BIRB796 from PYK2 (cyan) with corresponding gatekeeper residues. D, β-turn conformation in the hinge region with hydrogen bonds in dashes; Apo structure (pink), PYK2:BIRB796 complex (cyan), and PYK2:PF-4618433 (green).

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2009, 284, 13193-13201) copyright 2009.

Figures were selected by an automated process.