4OON

Crystal structure of PBP1a in complex with compound 17 ((4Z,8S,11E,14S)-5-(2-amino-1,3-thiazol-4-yl)-14-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-formyl-2-methyl-6-oxo-3,10-dioxa-4,7,11-triazatetradeca-4,11-diene-2,12,14-tricarboxylic acid)

Summary for 4OON

• Entry DOI: 10.2210/pdb4oon/pdb
• Related: 4OOL 4OOM
• Descriptor: Penicillin-binding protein 1A, (4Z,8S,11E,14S)-5-(2-amino-1,3-thiazol-4-yl)-14-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-formyl-2-methyl-6-oxo-3,10-dioxa-4,7,11-triazatetradeca-4,11-diene-2,12,14-tricarboxylic acid (3 entities in total)
• Functional Keywords: pbp1a, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Pseudomonas aeruginosa PAO1
• Cellular location: Cell inner membrane; Single-pass type II membrane protein (By similarity): Q07806
• Total number of polymer chains: 1
• Total formula weight: 89044.30

Authors

Han, S.,Caspers, N.,Knafels, J.D. (deposition date: 2014-02-03, release date: 2014-05-07, Last modification date: 2024-11-20)

Primary citation

Starr, J.,Brown, M.F.,Aschenbrenner, L.,Caspers, N.,Che, Y.,Gerstenberger, B.S.,Huband, M.,Knafels, J.D.,Lemmon, M.M.,Li, C.,McCurdy, S.P.,McElroy, E.,Rauckhorst, M.R.,Tomaras, A.P.,Young, J.A.,Zaniewski, R.P.,Shanmugasundaram, V.,Han, S.
Siderophore receptor-mediated uptake of lactivicin analogues in gram-negative bacteria.
J.Med.Chem., 57:3845-3855, 2014

PubMed Abstract: Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.

PubMed: 24694215
DOI: 10.1021/jm500219c

Experimental method

X-RAY DIFFRACTION (3.2 Å)