PDBsum entry 3vhk

Transferase

PDB id: 3vhk

Contents

Protein chain

297 a.a.

Ligands

BPK

EDO

Waters ×42

PDB id:

3vhk

Name:

Transferase

Title:

Crystal structure of the vegfr2 kinase domain in complex with a back pocket binder

Structure:

Vascular endothelial growth factor receptor 2. Chain: a. Fragment: unp residues 806-1171. Synonym: vegfr-2, fetal liver kinase 1, flk-1, kinase insert domain receptor, protein-tyrosine kinase receptor flk-1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.49Å R-factor: 0.210 R-free: 0.262

Authors:

H.Iwata,H.Oki,K.Okada,T.Takagi,M.Tawada,Y.Miyazaki,S.Imamura,A.Hori, M.S.Hixon,H.Kimura,H.Miki

Key ref:

H.Iwata et al. (2012). A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases. Acs Med Chem Lett, 3, 342-346. PubMed id: 24900475 DOI: 10.1021/ml3000403

Date:

25-Aug-11 Release date: 05-Sep-12

Protein chain

P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens

Seq: 1356 a.a.

Struc: 297 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⁺

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

Added reference

DOI no: 10.1021/ml3000403

Acs Med Chem Lett 3:342-346 (2012)

PubMed id: 24900475

A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases.

H.Iwata, H.Oki, K.Okada, T.Takagi, M.Tawada, Y.Miyazaki, S.Imamura, A.Hori, J.D.Lawson, M.S.Hixon, H.Kimura, H.Miki.

ABSTRACT

We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket-binding or hinge-binding). Next, fragments with the appropriate binding profile are assayed in combination with a known hinge-binding fragment and subsequently with a known back pocket-binding fragment. Confirmation of back pocket-binding by Yonetani-Theorell plot analysis progresses candidate fragments to crystallization trials. The method is exemplified by a fragment screening campaign against vascular endothelial growth factor receptor 2, and a novel back pocket-binding fragment is presented.