PDBsum entry 3vhk

Transferase

PDB id: 3vhk

Contents

Protein chain

297 a.a.

Ligands

BPK

EDO

Waters ×42

References listed in PDB file

Key reference

• Title: A back-To-Front fragment-Based drug design search strategy targeting the dfg-Out pocket of protein tyrosine kinases.
• Authors: 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.
• Ref.: Acs Med Chem Lett, 2012, 3, 342-346. [DOI no: 10.1021/ml3000403]
• PubMed id: 24900475

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.