PDBsum entry: 2vxy

Cell cycle

PDB id: 2vxy

Contents

Protein chain

306 a.a. *

Ligands

CIT

Metals

__K

Waters ×317

* Residue conservation analysis

PDB id:

2vxy

Name:

Cell cycle

Title:

The structure of ftsz from bacillus subtilis at 1.7a resolution

Structure:

Cell division protein ftsz. Chain: a. Synonym: ftsz. Engineered: yes

Source:

Bacillus subtilis. Organism_taxid: 1423. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.7Å R-factor: 0.186 R-free: 0.218

Authors:

V.V.Barynin,P.J.Baker,D.W.Rice,S.E.Sedelnikova,D.J.Haydon, N.R.Stokes,R.Ure,G.Galbraith,J.M.Bennett,D.R.Brown, J.R.Heal,J.M.Sheridan,S.T.Aiwale,P.K.Chauhan,A.Srivastava, A.Taneja,I.Collins,J.Errington,L.G.Czaplewski

Key ref:

D.J.Haydon et al. (2008). An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science, 321, 1673-1675. PubMed id: 18801997 DOI: 10.1126/science.1159961

Date:

15-Jul-08 Release date: 30-Sep-08

Protein chain

P17865  (FTSZ_BACSU) -  Cell division protein FtsZ

Seq: 382 a.a.

Struc: 306 a.a.

 Gene Ontology (GO) functional annotation 

• Cellular component: protein complex (2 terms)
• Biological process: cell cycle (4 terms)
• Biochemical function: nucleotide binding (5 terms)

DOI no: 10.1126/science.1159961

Science 321:1673-1675 (2008)

PubMed id: 18801997

An inhibitor of FtsZ with potent and selective anti-staphylococcal activity.

D.J.Haydon, N.R.Stokes, R.Ure, G.Galbraith, J.M.Bennett, D.R.Brown, P.J.Baker, V.V.Barynin, D.W.Rice, S.E.Sedelnikova, J.R.Heal, J.M.Sheridan, S.T.Aiwale, P.K.Chauhan, A.Srivastava, A.Taneja, I.Collins, J.Errington, L.G.Czaplewski.

ABSTRACT

FtsZ is an essential bacterial guanosine triphosphatase and homolog of mammalian beta-tubulin that polymerizes and assembles into a ring to initiate cell division. We have created a class of small synthetic antibacterials, exemplified by PC190723, which inhibits FtsZ and prevents cell division. PC190723 has potent and selective in vitro bactericidal activity against staphylococci, including methicillin- and multi-drug-resistant Staphylococcus aureus. The putative inhibitor-binding site of PC190723 was mapped to a region of FtsZ that is analogous to the Taxol-binding site of tubulin. PC190723 was efficacious in an in vivo model of infection, curing mice infected with a lethal dose of S. aureus. The data validate FtsZ as a target for antibacterial intervention and identify PC190723 as suitable for optimization into a new anti-staphylococcal therapy.

Selected figure(s)

Figure 1.
Fig. 1. Characterization of the cell-division inhibitor PC190723. (A) Chemical structure of PC190723. (B) In vivo efficacy of PC190723 in a murine model of infection. Mice were inoculated intraperitoneally with a lethal inoculum of S. aureus ATCC 19636 at time zero. One hour after infection the animals received 3 mg/kg (light gray line), 10 mg/kg (mid-gray line), or 30 mg/kg (dark gray line) of PC190723; negative control (vehicle only; dashed black line); or 3 mg/kg of the control antibiotic vancomycin by SC (top) or IV (bottom) administration. Mortality was recorded daily for 7 days.

Figure 3.
Fig. 3. Interaction of PC190723 with FtsZ. Model of a section of the FtsZ protein showing the position of the proposed binding site of PC190723 (left) relative to the nucleotide-binding site (right). The side chains of residues forming the putative binding pocket are labeled and are shown in ball-and-stick representation. The protein backbone is shown as a light blue ribbon. H7 is highlighted in red. In this model, hydrogen bonds are formed between the phenoxy ether of PC190723 and R191 and Q192 (dashed yellow lines). Blue, nitrogen; yellow, sulphur; gray, carbon; red, oxygen.

The above figures are reprinted by permission from the AAAs: Science (2008, 321, 1673-1675) copyright 2008.

Figures were selected by an automated process.