PDBsum entry 3e7b

Hydrolase

PDB id: 3e7b

Contents

Protein chains

294 a.a. *

Ligands

E7B ×2

GOL

AZI ×6

Metals

_MN ×4

_CL

_NA

Waters ×487

* Residue conservation analysis

PDB id:

3e7b

Name:

Hydrolase

Title:

Crystal structure of protein phosphatase-1 bound to the natural toxin inhibitor tautomycin

Structure:

Serine/threonine-protein phosphatase pp1-alpha catalytic subunit. Chain: a, b. Fragment: residues 7-300. Synonym: pp-1a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp1ca, ppp1a. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.70Å R-factor: 0.154 R-free: 0.175

Authors:

M.S.Kelker,R.Page,W.Peti

Key ref:

M.S.Kelker et al. (2009). Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors. J Mol Biol, 385, 11-21. PubMed id: 18992256 DOI: 10.1016/j.jmb.2008.10.053

Date:

18-Aug-08 Release date: 04-Nov-08

Protein chains

P62136  (PP1A_HUMAN) -  Serine/threonine-protein phosphatase PP1-alpha catalytic subunit from Homo sapiens

Seq: 330 a.a.

Struc: 294 a.a.*

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

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: 10.1016/j.jmb.2008.10.053

J Mol Biol 385:11-21 (2009)

PubMed id: 18992256

Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors.

M.S.Kelker, R.Page, W.Peti.

ABSTRACT

Protein phosphatase 1 occurs in all tissues and regulates many pathways, ranging from cell-cycle progression to carbohydrate metabolism. Many naturally occurring, molecular toxins modulate PP1 activity, though the exact mechanism of this differential regulation is not understood. A detailed elucidation of these interactions is crucial for understanding the cellular basis of phosphatase function and signaling pathways but, more importantly, they can serve as the basis for highly specific therapeutics, e.g. against cancer. We report the crystal structures of PP1 in complex with nodularin-R at 1.63 A and tautomycin at 1.70 A resolution. The PP1:nodularin-R complex was used to demonstrate the utility of our improved PP1 production technique, which produces highly active, soluble PP1. Tautomycin is one of the few toxins that reportedly preferentially binds PP1>PP2A. Therefore, the PP1:tautomycin structure is the first complex structure with a toxin with preferred PP1 specificity. Furthermore, since tautomycin is a linear non-peptide-based toxin, our reported structure will aid the design of lead compounds for novel PP1-specific pharmaceuticals.

Selected figure(s)

Figure 1.
Fig. 1. Structures of nodularin-R (a), tautomycin (b), tautomycetin (c) and cantharidin (d). Important interaction sites with PP1 identified in this study are highlighted. An asterisk marks the critical OH group in tautomycin. Details are given in the text.

Figure 4.
Fig. 4. PP1: cantharidin model. (a) Hydrogen bond interaction network on cantharidin and the PP1 active site. PP1 residues Y272, R221, and R96 make critical stabilizing interactions. (b) Surface representation of the PP1:canthardin model. Four surface pockets that can potentially be used to tether cantharidin-based inhibitors on PP1 are highlighted.

The above figures are reprinted from an Open Access publication published by Elsevier: J Mol Biol (2009, 385, 11-21) copyright 2009.

Figures were selected by an automated process.