PDBsum entry: 2bdx

Hydrolase/hydrolase inhibitor

PDB id: 2bdx

Contents

Protein chain

293 a.a. *

Ligands

DAL-LEU-ACB-ALA-1ZN-FGA-MAA

Metals

_MN ×2

Waters ×35

* Residue conservation analysis

PDB id:

2bdx

Name:

Hydrolase/hydrolase inhibitor

Title:

X-ray crystal structure of dihydromicrocystin-la bound to pr phosphatase-1

Structure:

Serine/threonine protein phosphatase pp1-gamma ca subunit. Chain: a. Synonym: pp-1g, protein phosphatase 1c catalytic subunit. Engineered: yes. Dihydromicrocystin-la. Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp1cc. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Resolution:

2.30Å R-factor: 0.214 R-free: 0.250

Authors:

J.T.Maynes,H.A.Luu,M.M.Cherney,R.J.Andersen,D.Williams,C.F.H M.N.James

Key ref:

J.T.Maynes et al. (2006). Crystal structures of protein phosphatase-1 bound to motuporin and dihydromicrocystin-LA: elucidation of the mechanism of enzyme inhibition by cyanobacterial toxins. J Mol Biol, 356, 111-120. PubMed id: 16343532 DOI: 10.1016/j.jmb.2005.11.019

Date:

21-Oct-05 Release date: 17-Jan-06

Protein chain

P36873  (PP1G_HUMAN) -  Serine/threonine-protein phosphatase PP1-gamma catalytic subunit

Seq: 323 a.a.

Struc: 293 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.3.16 - Phosphoprotein phosphatase.
• Reaction: A phosphoprotein + H₂O = a protein + phosphate

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

 Gene Ontology (GO) functional annotation 

• Cellular component: PTW/PP1 phosphatase complex (17 terms)
• Biological process: cell cycle (11 terms)
• Biochemical function: protein binding (6 terms)

Added reference

DOI no: 10.1016/j.jmb.2005.11.019

J Mol Biol 356:111-120 (2006)

PubMed id: 16343532

Crystal structures of protein phosphatase-1 bound to motuporin and dihydromicrocystin-LA: elucidation of the mechanism of enzyme inhibition by cyanobacterial toxins.

J.T.Maynes, H.A.Luu, M.M.Cherney, R.J.Andersen, D.Williams, C.F.Holmes, M.N.James.

ABSTRACT

The microcystins and nodularins are tumour promoting hepatotoxins that are responsible for global adverse human health effects and wildlife fatalities in countries where drinking water supplies contain cyanobacteria. The toxins function by inhibiting broad specificity Ser/Thr protein phosphatases in the host cells, thereby disrupting signal transduction pathways. A previous crystal structure of a microcystin bound to the catalytic subunit of protein phosphatase-1 (PP-1c) showed distinct changes in the active site region when compared with protein phosphatase-1 structures bound to other toxins. We have elucidated the crystal structures of the cyanotoxins, motuporin (nodularin-V) and dihydromicrocystin-LA bound to human protein phosphatase-1c (gamma isoform). The atomic structures of these complexes reveal the structural basis for inhibition of protein phosphatases by these toxins. Comparisons of the structures of the cyanobacterial toxin:phosphatase complexes explain the biochemical mechanism by which microcystins but not nodularins permanently modify their protein phosphatase targets by covalent addition to an active site cysteine residue.

Selected figure(s)

Figure 1.
Figure 1. Chemical structure of the cyanobacterial toxins. (a) Structure of dihydromicrocystin-LA (MCLA-2H). #The two sites of modification for the microcystins, in MCLA-2H these sites are Leu and Ala and in MCLR these sites are Leu and Arg. *The site of hydrogenation that removes the N-methyldehydroalanine residue and creates an N-methylalanine residue with no Michael addition properties. The 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid (Adda) residue includes all of the hydrophobic tail region of the inhibitor. (b) Structure of motuporin (nodularin-V). The Adda residue includes all of the hydrophobic tail region of the inhibitor. (c) Structure of nodularin-R.

Figure 5.
Figure 5. Comparison of PP-1c structures bound to toxins. (a) Stereo representation of the overlay of PP-1c bound to MCLA-2H (blue), MOT (green) and MCLR (orange).15 Motuporin is shown as sticks and the b[12]-b[13] loop is labeled. (b) Stereo representation of the active site regions of the PP-1c-bound toxin structures. The b-methylaspartic acid (Masp), g-linked d-glutamic acid and N-methyldehydroalanine (Nmda) residues are labeled. In MCLA-2H, the N-methylalanine residue and in MOT, the N-methyldehydrobutyrine residues are both in the equivalent position to Nmda. The disulphide bond between the Nmda residue of MCLR and C273 is shown. Colouring is the same as in (a).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 356, 111-120) copyright 2006.

Figures were selected by an automated process.