2aq7: Difference between revisions

Line 1:

[[Image:2aq7.gif|left|200px]]<br /><applet load="2aq7" size="~~450~~" color="white" frame="true" align="right" spinBox="true"

[[Image:2aq7.gif|left|200px]]<br /><applet load="2aq7" size="350" color="white" frame="true" align="right" spinBox="true"

caption="2aq7, resolution 2.30Å" />

'''Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli'''<br />

==Overview==

Thiolactomycin inhibits bacterial cell growth through inhibition of the, beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The, effect of modifications of the 5-position isoprenoid side chain on both, IC(50) and MIC were determined. Synthesis and screening of a structurally, diverse set of 5-position analogues revealed very little tolerance for, substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as, reducing one or both double bonds of the diene were not tolerated. The, only permissible structural modifications were removal of the isoprene, methyl group or addition of a methyl group to the terminus., Cocrystallization of these two inhibitors with the condensing enzyme from, Escherichia coli revealed that they retained the TLM binding mode at the, active site with reduced affinity. These results suggest a strict, requirement for a conjugated, planar side chain inserting within the, condensing enzyme active site.

Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.

==About this Structure==

2AQ7 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 TL5 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://~~ispc~~.weizmann.ac.il/oca-bin/ocashort?id=2AQ7 OCA].

2AQ7 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=TL5:'>TL5</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AQ7 OCA].

==Reference==

Line 14:

[[Category: Escherichia coli]]

[[Category: Single protein]]

[[Category: Boshoff, H.I.]]

[[Category: Boshoff, H I.]]

[[Category: Goodwin, M.B.]]

[[Category: Goodwin, M B.]]

[[Category: Kim, P.]]

[[Category: Lonsdale, J.]]

[[Category: Manjunatha, U.H.]]

[[Category: Manjunatha, U H.]]

[[Category: Miller, D.J.]]

[[Category: Miller, D J.]]

[[Category: Nguyen, Q.A.]]

[[Category: Nguyen, Q A.]]

[[Category: Price, A.C.]]

[[Category: Price, A C.]]

[[Category: Shenoy, G.]]

[[Category: Zhang, Y.M.]]

[[Category: Zhang, Y M.]]

[[Category: TL5]]

[[Category: fabb-ligand active-site complex]]

''Page seeded by [http://~~ispc~~.weizmann.ac.il/oca OCA ] on ~~Wed Nov~~ 21 08:17:~~30 2007~~''

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:45 2008''

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@@ Line 1: / Line 1: @@
-[[Image:2aq7.gif|left|200px]]<br /><applet load="2aq7" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2aq7.gif|left|200px]]<br /><applet load="2aq7" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2aq7, resolution 2.30&Aring;" />
 '''Structure-activity relationships at the 5-posiiton of thiolactomycin: an intact 5(R)-isoprene unit is required for activity against the condensing enzymes from Mycobacterium tuberculosis and Escherichia coli'''<br />
 ==Overview==
-Thiolactomycin inhibits bacterial cell growth through inhibition of the, beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The, effect of modifications of the 5-position isoprenoid side chain on both, IC(50) and MIC were determined. Synthesis and screening of a structurally, diverse set of 5-position analogues revealed very little tolerance for, substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as, reducing one or both double bonds of the diene were not tolerated. The, only permissible structural modifications were removal of the isoprene, methyl group or addition of a methyl group to the terminus., Cocrystallization of these two inhibitors with the condensing enzyme from, Escherichia coli revealed that they retained the TLM binding mode at the, active site with reduced affinity. These results suggest a strict, requirement for a conjugated, planar side chain inserting within the, condensing enzyme active site.
+Thiolactomycin inhibits bacterial cell growth through inhibition of the beta-ketoacyl-ACP synthase activity of type II fatty acid synthases. The effect of modifications of the 5-position isoprenoid side chain on both IC(50) and MIC were determined. Synthesis and screening of a structurally diverse set of 5-position analogues revealed very little tolerance for substitution in purified enzyme assays, but a few analogues retained MIC, presumably through another target. Even subtle modifications such as reducing one or both double bonds of the diene were not tolerated. The only permissible structural modifications were removal of the isoprene methyl group or addition of a methyl group to the terminus. Cocrystallization of these two inhibitors with the condensing enzyme from Escherichia coli revealed that they retained the TLM binding mode at the active site with reduced affinity. These results suggest a strict requirement for a conjugated, planar side chain inserting within the condensing enzyme active site.
 ==About this Structure==
-AQ7 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 TL5 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2AQ7 OCA].
+AQ7 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=TL5:'>TL5</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-ketoacyl-acyl-carrier-protein_synthase_I Beta-ketoacyl-acyl-carrier-protein synthase I], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.41 2.3.1.41] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AQ7 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Escherichia coli]]
 [[Category: Single protein]]
-[[Category: Boshoff, H.I.]]
+[[Category: Boshoff, H I.]]
-[[Category: Goodwin, M.B.]]
+[[Category: Goodwin, M B.]]
 [[Category: Kim, P.]]
 [[Category: Lonsdale, J.]]
-[[Category: Manjunatha, U.H.]]
+[[Category: Manjunatha, U H.]]
-[[Category: Miller, D.J.]]
+[[Category: Miller, D J.]]
-[[Category: Nguyen, Q.A.]]
+[[Category: Nguyen, Q A.]]
-[[Category: Price, A.C.]]
+[[Category: Price, A C.]]
 [[Category: Shenoy, G.]]
-[[Category: Zhang, Y.M.]]
+[[Category: Zhang, Y M.]]
 [[Category: TL5]]
 [[Category: fabb-ligand active-site complex]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 08:17:30 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:29:45 2008''