PDBsum entry 3o4s

Hydrolase

PDB id: 3o4s

Contents

Protein chain

293 a.a. *

Ligands

SO4 ×6

GOL ×5

Waters ×277

* Residue conservation analysis

PDB id:

3o4s

Name:

Hydrolase

Title:

Crystal structure of heptp with a closed wpd loop and an ordered e- loop

Structure:

Tyrosine-protein phosphatase non-receptor type 7. Chain: a. Fragment: unp residues 65-360. Synonym: protein-tyrosine phosphatase lc-ptp, hematopoietic protein- tyrosine phosphatase, heptp. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptpn7. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.90Å R-factor: 0.164 R-free: 0.212

Authors:

D.A.Critton,R.Page

Key ref:

D.A.Critton et al. (2011). Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop. J Mol Biol, 405, 619-629. PubMed id: 21094165

Date:

27-Jul-10 Release date: 24-Nov-10

Protein chain

P35236  (PTN7_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 7 from Homo sapiens

Seq: 360 a.a.

Struc: 293 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.1.3.48 - protein-tyrosine-phosphatase.
• Reaction: O-phospho-L-tyrosyl-[protein] + H2O = L-tyrosyl-[protein] + phosphate

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

Key reference

J Mol Biol 405:619-629 (2011)

PubMed id: 21094165

Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop.

D.A.Critton, L.Tautz, R.Page.

ABSTRACT

Phosphotyrosine hydrolysis by protein tyrosine phosphatases (PTPs) involves substrate binding by the PTP loop and closure over the active site by the WPD loop. The E loop, located immediately adjacent to the PTP and WPD loops, is conserved among human PTPs in both sequence and structure, yet the role of this loop in substrate binding and catalysis is comparatively unexplored. Hematopoietic PTP (HePTP) is a member of the kinase interaction motif (KIM) PTP family. Compared to other PTPs, KIM-PTPs have E loops that are unique in both sequence and structure. In order to understand the role of the E loop in the transition between the closed state and the open state of HePTP, we identified a novel crystal form of HePTP that allowed the closed-state-to-open-state transition to be observed within a single crystal form. These structures, which include the first structure of the HePTP open state, show that the WPD loop adopts an 'atypically open' conformation and, importantly, that ligands can be exchanged at the active site, which is critical for HePTP inhibitor development. These structures also show that tetrahedral oxyanions bind at a novel secondary site and function to coordinate the PTP, WPD, and E loops. Finally, using both structural and kinetic data, we reveal a novel role for E-loop residue Lys182 in enhancing HePTP catalytic activity through its interaction with Asp236 of the WPD loop, providing the first evidence for the coordinated dynamics of the WPD and E loops in the catalytic cycle, which, as we show, is relevant to multiple PTP families.