PDBsum entry 4glw

Ligase/ligase inhibitor

PDB id: 4glw

Contents

Protein chains

275 a.a.

Ligands

SO4 ×2

0XT ×2

NMN

Waters ×110

PDB id:

4glw

Name:

Ligase/ligase inhibitor

Title:

DNA ligase a in complex with inhibitor

Structure:

DNA ligase. Chain: a, b. Synonym: polydeoxyribonucleotide synthase [nad(+)]. Engineered: yes

Source:

Streptococcus pneumoniae. Organism_taxid: 488223. Strain: p1031. Gene: liga, spp_1122. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.209 R-free: 0.260

Authors:

L.Prade,R.Lange,N.Tidten-Luksch,A.Chambovey

Key ref:

J.P.Surivet et al. (2012). Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity. Bioorg Med Chem Lett, 22, 6705-6711. PubMed id: 23006603

Date:

15-Aug-12 Release date: 10-Oct-12

Protein chains

C1CKI0  (DNLJ_STRZP) -  DNA ligase from Streptococcus pneumoniae (strain P1031)

Seq: 652 a.a.

Struc: 275 a.a.*

* PDB and UniProt seqs differ at 6 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.6.5.1.2 - Dna ligase (NAD(+)).
• Reaction: NAD⁺ + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho- (deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP + beta- nicotinamide D-nucleotide

NAD(+) + (deoxyribonucleotide)n-3'-hydroxyl + 5'-phospho- (deoxyribonucleotide)m = (deoxyribonucleotide)n+m + AMP (Bound ligand (Het Group name = NMN) matches with 73.08% similarity) + beta- nicotinamide D-nucleotide

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

reference

Bioorg Med Chem Lett 22:6705-6711 (2012)

PubMed id: 23006603

Structure-guided design, synthesis and biological evaluation of novel DNA ligase inhibitors with in vitro and in vivo anti-staphylococcal activity.

J.P.Surivet, R.Lange, C.Hubschwerlen, W.Keck, J.L.Specklin, D.Ritz, D.Bur, H.Locher, P.Seiler, D.S.Strasser, L.Prade, C.Kohl, C.Schmitt, G.Chapoux, E.Ilhan, N.Ekambaram, A.Athanasiou, A.Knezevic, D.Sabato, A.Chambovey, M.Gaertner, M.Enderlin, M.Boehme, V.Sippel, P.Wyss.

ABSTRACT

A series of 2-amino-[1,8]-naphthyridine-3-carboxamides (ANCs) with potent inhibition of bacterial NAD(+)-dependent DNA ligases (LigAs) evolved from a 2,4-diaminopteridine derivative discovered by HTS. The design was guided by several highly resolved X-ray structures of our inhibitors in complex with either Streptococcus pneumoniae or Escherichia coli LigA. The structure-activity-relationship based on the ANC scaffold is discussed. The in-depth characterization of 2-amino-6-bromo-7-(trifluoromethyl)-[1,8]-naphthyridine-3-carboxamide, which displayed promising in vitro (MIC Staphylococcus aureus 1mg/L) and in vivo anti-staphylococcal activity, is presented.