6rmf: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6rmf is ~~ON HOLD until Paper~~ Publication

==Crystal structure of NDM-1 with VNRX-5133==

== Structural highlights ==

<table><tr><td colspan='2'>[[6rmf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RMF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RMF FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K9B:3-[2-[4-(2-azanylethylamino)cyclohexyl]ethanoylamino]-2,2-bis(oxidanyl)-3,4-dihydro-1,2$l^{4}-benzoxaborinine-8-carboxylic+acid'>K9B</scene>, <scene name='pdbligand=K9K:5-[[4-(2-azanylethylamino)cyclohexyl]methyl]-3-oxidanyl-2,4-dioxa-6-aza-3$l^{4}-boratricyclo[7.4.0.0^{3,7}]trideca-1(13),5,9,11-tetraene-13-carboxylic+acid'>K9K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>

<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaNDM-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</td></tr>

<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6rmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rmf OCA], [http://pdbe.org/6rmf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rmf RCSB], [http://www.ebi.ac.uk/pdbsum/6rmf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rmf ProSAT]</span></td></tr>

</table>

== Function ==

[[http://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN]] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin.

== Publication Abstract from PubMed ==

The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of beta-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-beta-lactamases (SBLs) and some clinically important metallo-beta-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp(3)) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the "high-energy-intermediate" analogue approach for broad-spectrum beta-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.

~~Authors~~:

Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-beta-Lactamases.,Krajnc A, Brem J, Hinchliffe P, Calvopina K, Panduwawala TD, Lang PA, Kamps JJAG, Tyrrell JM, Widlake E, Saward BG, Walsh TR, Spencer J, Schofield CJ J Med Chem. 2019 Sep 26;62(18):8544-8556. doi: 10.1021/acs.jmedchem.9b00911. Epub, 2019 Sep 16. PMID:31454231<ref>PMID:31454231</ref>

~~Description~~:

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

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Beta-lactamase]]

[[Category: Large Structures]]

[[Category: Brem, J]]

[[Category: Hinchliffe, P]]

[[Category: Schofield, C J]]

[[Category: Spencer, J]]

[[Category: Antibiotic resistance]]

[[Category: Antimicrobial protein]]

[[Category: Inhibitor]]

[[Category: Metallo-beta-lactamase]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6rmf is ON HOLD  until Paper Publication
+==Crystal structure of NDM-1 with VNRX-5133==
+<StructureSection load='6rmf' size='340' side='right'caption='[[6rmf]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6rmf]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_pneumoniae"_(schroeter_1886)_flugge_1886 "bacillus pneumoniae" (schroeter 1886) flugge 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RMF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RMF FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K9B:3-[2-[4-(2-azanylethylamino)cyclohexyl]ethanoylamino]-2,2-bis(oxidanyl)-3,4-dihydro-1,2$l^{4}-benzoxaborinine-8-carboxylic+acid'>K9B</scene>, <scene name='pdbligand=K9K:5-[[4-(2-azanylethylamino)cyclohexyl]methyl]-3-oxidanyl-2,4-dioxa-6-aza-3$l^{4}-boratricyclo[7.4.0.0^{3,7}]trideca-1(13),5,9,11-tetraene-13-carboxylic+acid'>K9K</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaNDM-1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=573 "Bacillus pneumoniae" (Schroeter 1886) Flugge 1886])</td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6rmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rmf OCA], [http://pdbe.org/6rmf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rmf RCSB], [http://www.ebi.ac.uk/pdbsum/6rmf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rmf ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN]] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of beta-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-beta-lactamases (SBLs) and some clinically important metallo-beta-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp(3)) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the "high-energy-intermediate" analogue approach for broad-spectrum beta-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.
-Authors:
+Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-beta-Lactamases.,Krajnc A, Brem J, Hinchliffe P, Calvopina K, Panduwawala TD, Lang PA, Kamps JJAG, Tyrrell JM, Widlake E, Saward BG, Walsh TR, Spencer J, Schofield CJ J Med Chem. 2019 Sep 26;62(18):8544-8556. doi: 10.1021/acs.jmedchem.9b00911. Epub, 2019 Sep 16. PMID:31454231<ref>PMID:31454231</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6rmf" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Beta-lactamase]]
+[[Category: Large Structures]]
+[[Category: Brem, J]]
+[[Category: Hinchliffe, P]]
+[[Category: Schofield, C J]]
+[[Category: Spencer, J]]
+[[Category: Antibiotic resistance]]
+[[Category: Antimicrobial protein]]
+[[Category: Inhibitor]]
+[[Category: Metallo-beta-lactamase]]