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| - | [[Image:1nnr.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_1nnr| PDB=1nnr | SCENE= }} | | {{STRUCTURE_1nnr| PDB=1nnr | SCENE= }} |
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| - | '''Crystal structure of a probable fosfomycin resistance protein (PA1129) from Pseudomonas aeruginosa with sulfate present in the active site'''
| + | ===Crystal structure of a probable fosfomycin resistance protein (PA1129) from Pseudomonas aeruginosa with sulfate present in the active site=== |
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| - | ==Overview==
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| - | Fosfomycin [(1R,2S)-epoxypropylphosphonic acid] is a simple phosphonate found to have antibacterial activity against both Gram-positive and Gram-negative microorganisms. Early resistance to the clinical use of the antibiotic was linked to a plasmid-encoded resistance protein, FosA, that catalyzes the addition of glutathione to the oxirane ring, rendering the antibiotic inactive. Subsequent studies led to the discovery of a genomically encoded homologue in the pathogen Pseudomonas aeruginosa. The proteins are Mn(II)-dependent enzymes where the metal is proposed to act as a Lewis acid stabilizing the negative charge that develops on the oxirane oxygen in the transition state. Several simple phosphonates, including the antiviral compound phosphonoformate (K(i) = 0.4 +/- 0.1 microM, K(d) approximately 0.2 microM), are shown to be inhibitors of FosA. The crystal structure of FosA from P. aeruginosa with phosphonoformate bound in the active site has been determined at 0.95 A resolution and reveals that the inhibitor forms a five-coordinate complex with the Mn(II) center with a geometry similar to that proposed for the transition state of the reaction. Binding studies show that phosphonoformate has a near-diffusion-controlled on rate (k(on) approximately 10(7)-10(8) M(-1) s(-1)) and an off rate (k(off) = 5 s(-1)) that is slower than that for fosfomycin (k(off) = 30 s(-1)). Taken together, these data suggest that the FosA-catalyzed reaction has a very early transition state and phosphonoformate acts as a minimal transition state analogue inhibitor.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15504029}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15504029 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15504029}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Manganese binding]] | | [[Category: Manganese binding]] |
| | [[Category: Potassium binding loop]] | | [[Category: Potassium binding loop]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:45:25 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 06:02:28 2008'' |
Revision as of 03:02, 28 July 2008
Template:STRUCTURE 1nnr
Crystal structure of a probable fosfomycin resistance protein (PA1129) from Pseudomonas aeruginosa with sulfate present in the active site
Template:ABSTRACT PUBMED 15504029
About this Structure
1NNR is a Single protein structure of sequence from Pseudomonas aeruginosa pao1. Full crystallographic information is available from OCA.
Reference
Phosphonoformate: a minimal transition state analogue inhibitor of the fosfomycin resistance protein, FosA., Rigsby RE, Rife CL, Fillgrove KL, Newcomer ME, Armstrong RN, Biochemistry. 2004 Nov 2;43(43):13666-73. PMID:15504029
Page seeded by OCA on Mon Jul 28 06:02:28 2008
