دورية أكاديمية
أعرض في EDS

Role of a solvent-exposed tryptophan in the recognition and binding of antibiotic substrates for a metallo-beta-lactamase.

التفاصيل البيبلوغرافية
العنوان: Role of a solvent-exposed tryptophan in the recognition and binding of antibiotic substrates for a metallo-beta-lactamase.
المؤلفون: Huntley JJ; Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA., Fast W, Benkovic SJ, Wright PE, Dyson HJ
المصدر: Protein science : a publication of the Protein Society [Protein Sci] 2003 Jul; Vol. 12 (7), pp. 1368-75.
نوع المنشور: Journal Article; Research Support, U.S. Gov't, P.H.S.
اللغة: English
بيانات الدورية: Publisher: Cold Spring Harbor Laboratory Press Country of Publication: United States NLM ID: 9211750 Publication Model: Print Cited Medium: Print ISSN: 0961-8368 (Print) Linking ISSN: 09618368 NLM ISO Abbreviation: Protein Sci Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
مواضيع طبية MeSH: Anti-Bacterial Agents/*metabolism , Bacteroides fragilis/*enzymology , Enzyme Inhibitors/*chemistry , Tryptophan/*metabolism , beta-Lactamases/*metabolism, Anti-Bacterial Agents/chemistry ; Binding Sites ; Cephalosporins/chemistry ; Cephalosporins/metabolism ; Enzyme Inhibitors/metabolism ; Kinetics ; Ligands ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Protein Conformation ; Solvents/chemistry ; Substrate Specificity ; Tryptophan/chemistry ; Zinc ; beta-Lactamase Inhibitors ; beta-Lactamases/chemistry
مستخلص: Numerous X-ray crystal structures of the metallo-beta-lactamase from Bacteroides fragilis and related organisms show a beta-hairpin loop immediately adjacent to the active-site zinc atom(s). Both crystallographic and NMR information show that the end of this beta-hairpin loop, which contains a solvent exposed tryptophan residue, Trp49, is highly flexible in the absence of substrates or other ligands, giving rise in some of the X-ray structures to a lack of observable electron density in this region. We report an investigation of the role of this mobile, solvent-exposed tryptophan using site-directed mutagenesis, steady state kinetics measurements and characterization by NMR. Trp49 appears to have a role both in substrate binding and in promotion of catalysis. Substitution of this residue with a number of different side chains indicates that the binding interaction depends on the bulky hydrophobic and aromatic nature of the indole ring, which can provide relatively non-specific interactions with a variety of antibiotic substrates. In this way, the tryptophan at this position provides a large degree of the breadth of substrate specificity for the metallo-beta-lactamase. Previous studies established that the antibiotic binding site was sufficiently plastic that the derivatization of existing antibiotics is unlikely to result in the successful treatment of bacterial infections incorporating this resistance element. Rather, a more productive approach may be to design therapeutics directed towards this solvent-exposed tryptophan residue.
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معلومات مُعتمدة: P01 GM056879 United States GM NIGMS NIH HHS; GM 56879 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Anti-Bacterial Agents)
0 (Cephalosporins)
0 (Enzyme Inhibitors)
0 (Ligands)
0 (Solvents)
0 (beta-Lactamase Inhibitors)
8DUH1N11BX (Tryptophan)
EC 3.5.2.- (beta-lactamase IMP-1)
EC 3.5.2.6 (beta-Lactamases)
EWP54G0J8F (nitrocefin)
J41CSQ7QDS (Zinc)
تواريخ الأحداث: Date Created: 20030626 Date Completed: 20041102 Latest Revision: 20240323
رمز التحديث: 20240323
مُعرف محوري في PubMed: PMC2323931
DOI: 10.1110/ps.0305303
PMID: 12824483
قاعدة البيانات: MEDLINE
الوصف
تدمد:0961-8368
DOI:10.1110/ps.0305303