2jt2

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{{STRUCTURE_2jt2| PDB=2jt2 | SCENE= }}
{{STRUCTURE_2jt2| PDB=2jt2 | SCENE= }}
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'''Solution Structure of the Aquifex aeolicus LpxC- CHIR-090 complex'''
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===Solution Structure of the Aquifex aeolicus LpxC- CHIR-090 complex===
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==Overview==
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The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising antibiotic target. CHIR-090, the most potent LpxC inhibitor discovered to date, displays two-step time-dependent inhibition and kills a wide range of Gram-negative pathogens as effectively as ciprofloxacin or tobramycin. In this study, we report the solution structure of the LpxC-CHIR-090 complex. CHIR-090 exploits conserved features of LpxC that are critical for catalysis, including the hydrophobic passage and essential active-site residues. CHIR-090 is adjacent to, but does not occupy, the UDP-binding pocket of LpxC, suggesting that a fragment-based approach may facilitate further optimization of LpxC inhibitors. Additionally, we identified key residues in the Insert II hydrophobic passage that modulate time-dependent inhibition and CHIR-090 resistance. CHIR-090 shares a similar, although previously unrecognized, chemical scaffold with other small-molecule antibiotics such as L-161,240 targeting LpxC, and provides a template for understanding the binding mode of these inhibitors. Consistent with this model, we provide evidence that L-161,240 also occupies the hydrophobic passage.
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(as it appears on PubMed at http://www.pubmed.gov), where 18025458 is the PubMed ID number.
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{{ABSTRACT_PUBMED_18025458}}
==About this Structure==
==About this Structure==
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2JT2 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JT2 OCA].
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2JT2 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Aquifex_aeolicus Aquifex aeolicus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JT2 OCA].
==Reference==
==Reference==
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[[Category: Lipid a biosynthesis]]
[[Category: Lipid a biosynthesis]]
[[Category: Lipid synthesis]]
[[Category: Lipid synthesis]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 09:15:52 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 19:55:51 2008''

Revision as of 16:55, 27 July 2008

Image:2jt2.png

Template:STRUCTURE 2jt2

Solution Structure of the Aquifex aeolicus LpxC- CHIR-090 complex

Template:ABSTRACT PUBMED 18025458

About this Structure

2JT2 is a Single protein structure of sequence from Aquifex aeolicus. Full experimental information is available from OCA.

Reference

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding., Barb AW, Jiang L, Raetz CR, Zhou P, Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433-8. Epub 2007 Nov 19. PMID:18025458

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