1fsy: Difference between revisions

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== Structural highlights ==

<table><tr><td colspan='2'>[[1fsy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Ecoli Ecoli~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FSY FirstGlance]. <br>

<table><tr><td colspan='2'>[[1fsy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FSY FirstGlance]. <br>

</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=105:N~~-[~~5-METHYL-3-O-TOLYL-ISOXAZOLE-4-CARBOXYLIC+ACID+AMIDE~~]~~+BORONIC+ACID'>105</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>~~</td></tr>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr>

<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~|~~Related~~:]]</b></td><td class="sblockDat"><~~div style~~='~~overflow~~: ~~auto; max~~-~~height: 3em;'>~~[~~[2bls|2bls~~]~~], [[3bls|3bls]], [[1c3b|1c3b]], [[1fsw|1fsw]]</div~~></td><~~/tr>~~

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=105:N-[5-METHYL-3-O-TOLYL-ISOXAZOLE-4-CARBOXYLIC+ACID+AMIDE]+BORONIC+ACID'>105</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>

~~<tr id~~='~~activity'><td class~~=~~"sblockLbl"><b>Activity~~:~~</b></td><td class="sblockDat"><span class='plainlinks~~'>~~[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6]~~ </~~span~~></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1fsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fsy OCA], [https://pdbe.org/1fsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fsy RCSB], [https://www.ebi.ac.uk/pdbsum/1fsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fsy ProSAT]</span></td></tr>

</table>

== Function ==

[[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.

[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.

== Evolutionary Conservation ==

[[Image:Consurf_key_small.gif|200px|right]]

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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1fsy ConSurf].

~~<div style="background-color:#fffaf0;">~~

~~== Publication Abstract from PubMed ==~~

BACKGROUND: Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health. To understand how beta-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because beta-lactams form covalent adducts with beta-lactamases. This has complicated functional analyses and inhibitor design. RESULTS: To investigate the contribution to interaction energy of the key amide (R1) side chain of beta-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine beta-lactamases. Therefore, binding energies can be calculated directly from K(i) values. The K(i) values measured span four orders of magnitude against the Group I beta-lactamase AmpC and three orders of magnitude against the Group II beta-lactamase TEM-1. The acylglycineboronic acids have K(i) values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of beta-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of beta-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to beta-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 A and 1.75 A resolution; these structures suggest interactions that are important to the affinity of the inhibitors. CONCLUSIONS: Acylglycineboronic acids allow us to begin to dissect interaction energies between beta-lactam side chains and beta-lactamases. Surprisingly, there is little correlation between the affinity contributed by R1 side chains and their occurrence in beta-lactam inhibitors or beta-lactam substrates of serine beta-lactamases. Nevertheless, presented in acylglycineboronic acids, these side chains can lead to inhibitors with high affinities and specificities. The structures of their complexes with AmpC give a molecular context to their affinities and may guide the design of anti-resistance compounds in this series.

Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases.,Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK Chem Biol. 2001 Jan;8(1):17-31. PMID:11182316<ref>PMID:11182316</ref>

~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~

~~</div>~~

~~<div class="pdbe-citations 1fsy" style="background-color:#fffaf0;"></div>~~

==See Also==

*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]

~~== References ==~~

~~<references/>~~

__TOC__

</StructureSection>

[[Category: ~~Beta~~-~~lactamase]]~~

[[Category: Escherichia coli K-12]]

~~[[Category: Ecoli~~]]

[[Category: Large Structures]]

[[Category: Blasczcak~~, L C~~]]

[[Category: Blasczcak LC]]

[[Category: Caselli, E]]

[[Category: Caselli E]]

[[Category: Powers~~, R A~~]]

[[Category: Powers RA]]

[[Category: Prati, F]]

[[Category: Prati F]]

[[Category: Shoichet~~, B K~~]]

[[Category: Shoichet BK]]

[[Category: Wu~~, C Y]]~~

[[Category: Wu CY]]

~~[[Category: Cephalosporinase]]~~

~~[[Category: Hydrolase]]~~

~~[[Category: Serine hydrolase~~]]

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@@ Line 3: / Line 3: @@
 <StructureSection load='1fsy' size='340' side='right'caption='[[1fsy]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1fsy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FSY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1fsy]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FSY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1FSY FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=105:N-[5-METHYL-3-O-TOLYL-ISOXAZOLE-4-CARBOXYLIC+ACID+AMIDE]+BORONIC+ACID'>105</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2bls|2bls]], [[3bls|3bls]], [[1c3b|1c3b]], [[1fsw|1fsw]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=105:N-[5-METHYL-3-O-TOLYL-ISOXAZOLE-4-CARBOXYLIC+ACID+AMIDE]+BORONIC+ACID'>105</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1fsy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fsy OCA], [https://pdbe.org/1fsy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1fsy RCSB], [https://www.ebi.ac.uk/pdbsum/1fsy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1fsy ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI]] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
+[https://www.uniprot.org/uniprot/AMPC_ECOLI AMPC_ECOLI] This protein is a serine beta-lactamase with a substrate specificity for cephalosporins.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 21: / Line 20: @@
 </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1fsy ConSurf].
 <div style="clear:both"></div>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-BACKGROUND: Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health. To understand how beta-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because beta-lactams form covalent adducts with beta-lactamases. This has complicated functional analyses and inhibitor design. RESULTS: To investigate the contribution to interaction energy of the key amide (R1) side chain of beta-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine beta-lactamases. Therefore, binding energies can be calculated directly from K(i) values. The K(i) values measured span four orders of magnitude against the Group I beta-lactamase AmpC and three orders of magnitude against the Group II beta-lactamase TEM-1. The acylglycineboronic acids have K(i) values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of beta-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of beta-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to beta-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 A and 1.75 A resolution; these structures suggest interactions that are important to the affinity of the inhibitors. CONCLUSIONS: Acylglycineboronic acids allow us to begin to dissect interaction energies between beta-lactam side chains and beta-lactamases. Surprisingly, there is little correlation between the affinity contributed by R1 side chains and their occurrence in beta-lactam inhibitors or beta-lactam substrates of serine beta-lactamases. Nevertheless, presented in acylglycineboronic acids, these side chains can lead to inhibitors with high affinities and specificities. The structures of their complexes with AmpC give a molecular context to their affinities and may guide the design of anti-resistance compounds in this series.
-Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases.,Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK Chem Biol. 2001 Jan;8(1):17-31. PMID:11182316<ref>PMID:11182316</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 1fsy" style="background-color:#fffaf0;"></div>
 ==See Also==
 *[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
-== References ==
-<references/>
 __TOC__
 </StructureSection>
-[[Category: Beta-lactamase]]
+[[Category: Escherichia coli K-12]]
-[[Category: Ecoli]]
 [[Category: Large Structures]]
-[[Category: Blasczcak, L C]]
+[[Category: Blasczcak LC]]
-[[Category: Caselli, E]]
+[[Category: Caselli E]]
-[[Category: Powers, R A]]
+[[Category: Powers RA]]
-[[Category: Prati, F]]
+[[Category: Prati F]]
-[[Category: Shoichet, B K]]
+[[Category: Shoichet BK]]
-[[Category: Wu, C Y]]
+[[Category: Wu CY]]
-[[Category: Cephalosporinase]]
-[[Category: Hydrolase]]
-[[Category: Serine hydrolase]]