PDBsum entry 5hpe

Hydrolase

PDB id: 5hpe

Contents

Protein chain

326 a.a.

Ligands

NCO ×2

Metals

_MN ×2

Waters ×105

PDB id:

5hpe

Name:

Hydrolase

Title:

Phosphatase domain of pp5 bound to a phosphomimetic cdc37 substrate peptide

Structure:

Serine/threonine-protein phosphatase 5,hsp90 co-chaperone cdc37. Chain: a. Synonym: pp5,protein phosphatase t,ppt. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp5c, ppp5, cdc37. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.27Å R-factor: 0.175 R-free: 0.236

Authors:

J.Oberoi,L.Mariotti,C.Vaughan

Key ref:

J.Oberoi et al. (2016). Structural and functional basis of protein phosphatase 5 substrate specificity. Proc Natl Acad Sci U S A, 113, 9009-9014. PubMed id: 27466404 DOI: 10.1073/pnas.1603059113

Date:

20-Jan-16 Release date: 27-Jul-16

Protein chain

P53041  (PPP5_HUMAN) -  Serine/threonine-protein phosphatase 5 from Homo sapiens

Seq: 499 a.a.

Struc: 326 a.a.*

Protein chain

Q16543  (CDC37_HUMAN) -  Hsp90 co-chaperone Cdc37 from Homo sapiens

Seq: 378 a.a.

Struc: 326 a.a.*

* PDB and UniProt seqs differ at 16 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.3.16 - protein-serine/threonine phosphatase.
• Reaction:
  1. O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate
  2. O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate

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

Added reference

DOI no: 10.1073/pnas.1603059113

Proc Natl Acad Sci U S A 113:9009-9014 (2016)

PubMed id: 27466404

Structural and functional basis of protein phosphatase 5 substrate specificity.

J.Oberoi, D.M.Dunn, M.R.Woodford, L.Mariotti, J.Schulman, D.Bourboulia, M.Mollapour, C.K.Vaughan.

ABSTRACT

The serine/threonine phosphatase protein phosphatase 5 (PP5) regulates hormone- and stress-induced cellular signaling by association with the molecular chaperone heat shock protein 90 (Hsp90). PP5-mediated dephosphorylation of the cochaperone Cdc37 is essential for activation of Hsp90-dependent kinases. However, the details of this mechanism remain unknown. We determined the crystal structure of a Cdc37 phosphomimetic peptide bound to the catalytic domain of PP5. The structure reveals PP5 utilization of conserved elements of phosphoprotein phosphatase (PPP) structure to bind substrate and provides a template for many PPP-substrate interactions. Our data show that, despite a highly conserved structure, elements of substrate specificity are determined within the phosphatase catalytic domain itself. Structure-based mutations in vivo reveal that PP5-mediated dephosphorylation is required for kinase and steroid hormone receptor release from the chaperone complex. Finally, our data show that hyper- or hypoactivity of PP5 mutants increases Hsp90 binding to its inhibitor, suggesting a mechanism to enhance the efficacy of Hsp90 inhibitors by regulation of PP5 activity in tumors.