2J7L

E. coli P Pilus chaperone PapD in complex with a pilus biogenesis inhibitor, pilicide 2c

Summary for 2J7L

• Entry DOI: 10.2210/pdb2j7l/pdb
• Related: 1N0L 1PDK 1QPP 1QPX 2J2Z 3DPA
• Descriptor: CHAPERONE PROTEIN PAPD, (3R)-8-CYCLOPROPYL-6-(MORPHOLIN-4-YLMETHYL)-7-(1-NAPHTHYLMETHYL)-5-OXO-2,3-DIHYDRO-5H-[1,3]THIAZOLO[3,2-A]PYRIDINE-3-CARBOXYLIC ACID (3 entities in total)
• Functional Keywords: fimbria, inhibitor, chaperone, periplasmic, immunoglobulin domain, chaperone/surface active protein, chaperone-surface active protein complex
• Biological source: ESCHERICHIA COLI
• Cellular location: Periplasm: P15319
• Total number of polymer chains: 1
• Total formula weight: 25052.46

Authors

Remaut, H.,Pinkner, J.S.,Hultgren, S.J.,Almqvist, F.,Waksman, G. (deposition date: 2006-10-12, release date: 2006-11-01, Last modification date: 2024-11-06)

Primary citation

Pinkner, J.S.,Remaut, H.,Buelens, F.,Miller, E.,Aberg, V.,Pemberton, N.,Hedenstrom, M.,Larsson, A.,Seed, P.,Waksman, G.,Hultgren, S.J.,Almqvist, F.
Rationally Designed Small Compounds Inhibit Pilus Biogenesis in Uropathogenic Bacteria.
Proc.Natl.Acad.Sci.USA, 103:17897-, 2006

PubMed Abstract: A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by approximately 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.

PubMed: 17098869
DOI: 10.1073/PNAS.0606795103

Experimental method

X-RAY DIFFRACTION (2.6 Å)