1g2a
From Proteopedia
(New page: 200px<br /><applet load="1g2a" size="450" color="white" frame="true" align="right" spinBox="true" caption="1g2a, resolution 1.75Å" /> '''THE CRYSTAL STRUCTUR...) |
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| - | [[Image:1g2a.gif|left|200px]]<br /><applet load="1g2a" size=" | + | [[Image:1g2a.gif|left|200px]]<br /><applet load="1g2a" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1g2a, resolution 1.75Å" /> | caption="1g2a, resolution 1.75Å" /> | ||
'''THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN'''<br /> | '''THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Peptide deformylase (PDF) is an essential bacterial metalloenzyme which | + | Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents. |
==About this Structure== | ==About this Structure== | ||
| - | 1G2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with NI and BB2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Formylmethionine_deformylase Formylmethionine deformylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.31 3.5.1.31] Full crystallographic information is available from [http:// | + | 1G2A is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=NI:'>NI</scene> and <scene name='pdbligand=BB2:'>BB2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Formylmethionine_deformylase Formylmethionine deformylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.31 3.5.1.31] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1G2A OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Formylmethionine deformylase]] | [[Category: Formylmethionine deformylase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Baker, P | + | [[Category: Baker, P J.]] |
[[Category: Barynin, V.]] | [[Category: Barynin, V.]] | ||
[[Category: Beckett, P.]] | [[Category: Beckett, P.]] | ||
[[Category: Brown, A.]] | [[Category: Brown, A.]] | ||
[[Category: Catlin, C.]] | [[Category: Catlin, C.]] | ||
| - | [[Category: Clements, J | + | [[Category: Clements, J M.]] |
| - | [[Category: Hunter, M | + | [[Category: Hunter, M G.]] |
[[Category: Lobell, M.]] | [[Category: Lobell, M.]] | ||
[[Category: Palan, S.]] | [[Category: Palan, S.]] | ||
| - | [[Category: Rice, D | + | [[Category: Rice, D W.]] |
| - | [[Category: Rodgers, H | + | [[Category: Rodgers, H F.]] |
[[Category: Thomas, W.]] | [[Category: Thomas, W.]] | ||
[[Category: Whittaker, M.]] | [[Category: Whittaker, M.]] | ||
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[[Category: polypeptide deformylase]] | [[Category: polypeptide deformylase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:45:15 2008'' |
Revision as of 10:45, 21 February 2008
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THE CRYSTAL STRUCTURE OF E.COLI PEPTIDE DEFORMYLASE COMPLEXED WITH ACTINONIN
Overview
Peptide deformylase (PDF) is an essential bacterial metalloenzyme which deformylates the N-formylmethionine of newly synthesized polypeptides and as such represents a novel target for antibacterial chemotherapy. To identify novel PDF inhibitors, we screened a metalloenzyme inhibitor library and identified an N-formyl-hydroxylamine derivative, BB-3497, and a related natural hydroxamic acid antibiotic, actinonin, as potent and selective inhibitors of PDF. To elucidate the interactions that contribute to the binding affinity of these inhibitors, we determined the crystal structures of BB-3497 and actinonin bound to Escherichia coli PDF at resolutions of 2.1 and 1.75 A, respectively. In both complexes, the active-site metal atom was pentacoordinated by the side chains of Cys 90, His 132, and His 136 and the two oxygen atoms of N-formyl-hydroxylamine or hydroxamate. BB-3497 had activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, and activity against some gram-negative bacteria. Time-kill analysis showed that the mode of action of BB-3497 was primarily bacteriostatic. The mechanism of resistance was via mutations within the formyltransferase gene, as previously described for actinonin. While actinonin and its derivatives have not been used clinically because of their poor pharmacokinetic properties, BB-3497 was shown to be orally bioavailable. A single oral dose of BB-3497 given 1 h after intraperitoneal injection of S. aureus Smith or methicillin-resistant S. aureus protected mice from infection with median effective doses of 8 and 14 mg/kg of body weight, respectively. These data validate PDF as a novel target for the design of a new generation of antibacterial agents.
About this Structure
1G2A is a Single protein structure of sequence from Escherichia coli with and as ligands. Active as Formylmethionine deformylase, with EC number 3.5.1.31 Full crystallographic information is available from OCA.
Reference
Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor., Clements JM, Beckett RP, Brown A, Catlin G, Lobell M, Palan S, Thomas W, Whittaker M, Wood S, Salama S, Baker PJ, Rodgers HF, Barynin V, Rice DW, Hunter MG, Antimicrob Agents Chemother. 2001 Feb;45(2):563-70. PMID:11158755
Page seeded by OCA on Thu Feb 21 12:45:15 2008
Categories: Escherichia coli | Formylmethionine deformylase | Single protein | Baker, P J. | Barynin, V. | Beckett, P. | Brown, A. | Catlin, C. | Clements, J M. | Hunter, M G. | Lobell, M. | Palan, S. | Rice, D W. | Rodgers, H F. | Thomas, W. | Whittaker, M. | BB2 | NI | Actinonin | Inhibition | Polypeptide deformylase
