PDBsum entry 1j4x

Hydrolase

PDB id: 1j4x

Contents

Protein chains

178 a.a. *

11 a.a. *

Waters ×66

* Residue conservation analysis

References listed in PDB file

Key reference

• Title: Structural basis for the recognition of a bisphosphorylated map kinase peptide by human vhr protein phosphatase.
• Authors: M.A.Schumacher, J.L.Todd, A.E.Rice, K.G.Tanner, J.M.Denu.
• Ref.: Biochemistry, 2002, 41, 3009-3017. [DOI no: 10.1021/bi015799l]
• PubMed id: 11863439

Abstract

Human VHR (vaccinia H1 related phosphatase) is a member of the dual-specificity phosphatases (DSPs) that often act on bisphosphorylated protein substrates. Unlike most DSPs, VHR displays a strong preference for dephosphorylating phosphotyrosine residues over phosphothreonine residues. Here we describe the 2.75 A crystal structure of the C124S inactive VHR mutant in complex with a bisphosphorylated peptide corresponding to the MAP kinase activation lip. This structure and subsequent biochemical studies revealed the basis for the strong preference for hydrolyzing phosphotyrosine within bisphosphorylated substrates containing -pTXpY-. In the structure, the two phospho residues are oriented into distinct pockets; the phosphotyrosine is bound in the exposed yet deep active site cleft while the phosphothreonine is loosely tethered into a nearby basic pocket containing Arg(158). As this structure is the first substrate-enzyme complex reported for the DSP family of enzymes, these results provide the first glimpse into how DSPs bind their protein substrates.