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1nki

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{{STRUCTURE_1nki| PDB=1nki | SCENE= }}
{{STRUCTURE_1nki| PDB=1nki | SCENE= }}
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'''CRYSTAL STRUCURE OF THE FOSFOMYCIN RESISTANCE PROTEIN A (FOSA) CONTAINING BOUND PHOSPHONOFORMATE'''
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===CRYSTAL STRUCURE OF THE FOSFOMYCIN RESISTANCE PROTEIN A (FOSA) CONTAINING BOUND PHOSPHONOFORMATE===
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 15504029 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15504029}}
==About this Structure==
==About this Structure==
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[[Category: Manganese binding]]
[[Category: Manganese binding]]
[[Category: Potassium binding loop]]
[[Category: Potassium binding loop]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 02:38:27 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 18:13:31 2008''

Revision as of 15:13, 27 July 2008

Image:1nki.png

Template:STRUCTURE 1nki

CRYSTAL STRUCURE OF THE FOSFOMYCIN RESISTANCE PROTEIN A (FOSA) CONTAINING BOUND PHOSPHONOFORMATE

Template:ABSTRACT PUBMED 15504029

About this Structure

1NKI 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 Sun Jul 27 18:13:31 2008

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