1g27: Difference between revisions

Revision as of 13:45, 21 February 2008

CRYSTAL STRUCTURE OF E.COLI POLYPEPTIDE DEFORMYLASE COMPLEXED WITH THE INHIBITOR BB-3497

OverviewOverview

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 StructureAbout this Structure

1G27 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.

ReferenceReference

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

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-[[Image:1g27.gif|left|200px]]<br /><applet load="1g27" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1g27.gif|left|200px]]<br /><applet load="1g27" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1g27, resolution 2.10&Aring;" />
 '''CRYSTAL STRUCTURE OF E.COLI POLYPEPTIDE DEFORMYLASE COMPLEXED WITH THE INHIBITOR BB-3497'''<br />
 ==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.
+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==
-G27 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 BB1 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1G27 OCA].
+G27 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=BB1:'>BB1</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=1G27 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Formylmethionine deformylase]]
 [[Category: Single protein]]
-[[Category: Baker, P.J.]]
+[[Category: Baker, P J.]]
 [[Category: Barynin, V.]]
 [[Category: Beckett, P.]]
 [[Category: Brown, A.]]
 [[Category: Catlin, C.]]
-[[Category: Clements, J.M.]]
+[[Category: Clements, J M.]]
-[[Category: Hunter, M.G.]]
+[[Category: Hunter, M G.]]
 [[Category: Lobell, M.]]
 [[Category: Palan, S.]]
-[[Category: Rice, D.W.]]
+[[Category: Rice, D W.]]
-[[Category: Rodgers, H.F.]]
+[[Category: Rodgers, H F.]]
 [[Category: Thomas, W.]]
 [[Category: Whittaker, M.]]
@@ Line 33: / Line 33: @@
 [[Category: polypeptide deformylase]]
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