1q2p
From Proteopedia
(New page: 200px<br /><applet load="1q2p" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q2p, resolution 2.00Å" /> '''SHV-1 class A beta-l...) |
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| - | [[Image:1q2p.gif|left|200px]]<br /><applet load="1q2p" size=" | + | [[Image:1q2p.gif|left|200px]]<br /><applet load="1q2p" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1q2p, resolution 2.00Å" /> | caption="1q2p, resolution 2.00Å" /> | ||
'''SHV-1 class A beta-lactamase complexed with penem WAY185229'''<br /> | '''SHV-1 class A beta-lactamase complexed with penem WAY185229'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The design and synthesis of a series of seven tricyclic 6-methylidene | + | The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization. |
==About this Structure== | ==About this Structure== | ||
| - | 1Q2P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae] with MA4 and WY2 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http:// | + | 1Q2P is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae] with <scene name='pdbligand=MA4:'>MA4</scene> and <scene name='pdbligand=WY2:'>WY2</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Q2P OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Klebsiella pneumoniae]] | [[Category: Klebsiella pneumoniae]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Bonomo, R | + | [[Category: Bonomo, R A.]] |
[[Category: Hujer, A.]] | [[Category: Hujer, A.]] | ||
| - | [[Category: Knox, J | + | [[Category: Knox, J R.]] |
| - | [[Category: Mansour, T | + | [[Category: Mansour, T S.]] |
[[Category: Nukaga, M.]] | [[Category: Nukaga, M.]] | ||
| - | [[Category: Venkatesan, A | + | [[Category: Venkatesan, A M.]] |
[[Category: MA4]] | [[Category: MA4]] | ||
[[Category: WY2]] | [[Category: WY2]] | ||
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[[Category: inhibition]] | [[Category: inhibition]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:35:12 2008'' |
Revision as of 12:35, 21 February 2008
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SHV-1 class A beta-lactamase complexed with penem WAY185229
Overview
The design and synthesis of a series of seven tricyclic 6-methylidene penems as novel class A and C serine beta-lactamase inhibitors is described. These compounds proved to be very potent inhibitors of the TEM-1 and AmpC beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. In combination with piperacillin, their in vitro activities enhanced susceptibility of all class C resistant strains from various bacteria. Crystallographic structures of a serine-bound reaction intermediate of 17 with the class A SHV-1 and class C GC1 enzymes have been established to resolutions of 2.0 and 1.4 A, respectively, and refined to R-factors equal 0.163 and 0.145. In both beta-lactamases, a seven-membered 1,4-thiazepine ring has formed. The stereogenic C7 atom in the ring has the R configuration in the SHV-1 intermediate and has both R and S configurations in the GC1 intermediate. Hydrophobic stacking interactions between the tricyclic C7 substituent and a tyrosine side chain, rather than electrostatic or hydrogen bonding by the C3 carboxylic acid group, dominate in both complexes. The formation of the 1,4- thiazepine ring structures is proposed based on a 7-endo-trig cyclization.
About this Structure
1Q2P is a Single protein structure of sequence from Klebsiella pneumoniae with and as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Structure-activity relationship of 6-methylidene penems bearing tricyclic heterocycles as broad-spectrum beta-lactamase inhibitors: crystallographic structures show unexpected binding of 1,4-thiazepine intermediates., Venkatesan AM, Gu Y, Dos Santos O, Abe T, Agarwal A, Yang Y, Petersen PJ, Weiss WJ, Mansour TS, Nukaga M, Hujer AM, Bonomo RA, Knox JR, J Med Chem. 2004 Dec 16;47(26):6556-68. PMID:15588091
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