1ll9: Difference between revisions

Revision as of 14:46, 21 February 2008

Crystal Structure Of AmpC beta-Lactamase From E. Coli In Complex With Amoxicillin

OverviewOverview

beta-lactamases confer resistance to beta-lactam antibiotics such as penicillins and cephalosporins. However, beta-lactams that form an acyl-intermediate with the enzyme but subsequently are hindered from forming a catalytically competent conformation seem to be inhibitors of beta-lactamases. This inhibition may be imparted by specific groups on the ubiquitous R(1) side chain of beta-lactams, such as the 2-amino-4-thiazolyl methoxyimino (ATMO) group common among third-generation cephalosporins. Using steric hindrance of deacylation as a design guide, penicillin and carbacephem substrates were converted into effective beta-lactamase inhibitors and antiresistance antibiotics. To investigate the structural bases of inhibition, the crystal structures of the acyl-adducts of the penicillin substrate amoxicillin and the new analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds in a catalytically incompetent conformation resembling that adopted by third-generation cephalosporins, demonstrating the transferability of such sterically hindered groups in inhibitor design.

About this StructureAbout this Structure

1LL9 is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.

ReferenceReference

Using steric hindrance to design new inhibitors of class C beta-lactamases., Trehan I, Morandi F, Blaszczak LC, Shoichet BK, Chem Biol. 2002 Sep;9(9):971-80. PMID:12323371

Page seeded by OCA on Thu Feb 21 13:45:59 2008

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-[[Image:1ll9.gif|left|200px]]<br /><applet load="1ll9" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1ll9.gif|left|200px]]<br /><applet load="1ll9" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1ll9, resolution 1.87&Aring;" />
 '''Crystal Structure Of AmpC beta-Lactamase From E. Coli In Complex With Amoxicillin'''<br />
 ==Overview==
-beta-lactamases confer resistance to beta-lactam antibiotics such as, penicillins and cephalosporins. However, beta-lactams that form an, acyl-intermediate with the enzyme but subsequently are hindered from, forming a catalytically competent conformation seem to be inhibitors of, beta-lactamases. This inhibition may be imparted by specific groups on the, ubiquitous R(1) side chain of beta-lactams, such as the, 2-amino-4-thiazolyl methoxyimino (ATMO) group common among, third-generation cephalosporins. Using steric hindrance of deacylation as, a design guide, penicillin and carbacephem substrates were converted into, effective beta-lactamase inhibitors and antiresistance antibiotics. To, investigate the structural bases of inhibition, the crystal structures of, the acyl-adducts of the penicillin substrate amoxicillin and the new, analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds, in a catalytically incompetent conformation resembling that adopted by, third-generation cephalosporins, demonstrating the transferability of such, sterically hindered groups in inhibitor design.
+beta-lactamases confer resistance to beta-lactam antibiotics such as penicillins and cephalosporins. However, beta-lactams that form an acyl-intermediate with the enzyme but subsequently are hindered from forming a catalytically competent conformation seem to be inhibitors of beta-lactamases. This inhibition may be imparted by specific groups on the ubiquitous R(1) side chain of beta-lactams, such as the 2-amino-4-thiazolyl methoxyimino (ATMO) group common among third-generation cephalosporins. Using steric hindrance of deacylation as a design guide, penicillin and carbacephem substrates were converted into effective beta-lactamase inhibitors and antiresistance antibiotics. To investigate the structural bases of inhibition, the crystal structures of the acyl-adducts of the penicillin substrate amoxicillin and the new analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds in a catalytically incompetent conformation resembling that adopted by third-generation cephalosporins, demonstrating the transferability of such sterically hindered groups in inhibitor design.
 ==About this Structure==
-LL9 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 AXL as [http://en.wikipedia.org/wiki/ligand ligand]. 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1LL9 OCA].
+LL9 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=AXL:'>AXL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=1LL9 OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Escherichia coli]]
 [[Category: Single protein]]
-[[Category: Blaszczak, L.C.]]
+[[Category: Blaszczak, L C.]]
 [[Category: Morandi, F.]]
-[[Category: Shoichet, B.K.]]
+[[Category: Shoichet, B K.]]
 [[Category: Trehan, I.]]
 [[Category: AXL]]
@@ Line 24: / Line 24: @@
 [[Category: serine]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 20:38:56 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:45:59 2008''