4u3b: Difference between revisions
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==LpxC from A.Aaeolicus in complex with the MMP inhibitor 4-[[4-(4-chlorophenoxy)phenyl]sulfanylmethyl]tetrahydropyran-4-carbohydroxamic acid - compound 2== | ==LpxC from A.Aaeolicus in complex with the MMP inhibitor 4-[[4-(4-chlorophenoxy)phenyl]sulfanylmethyl]tetrahydropyran-4-carbohydroxamic acid - compound 2== | ||
<StructureSection load='4u3b' size='340' side='right' caption='[[4u3b]], [[Resolution|resolution]] 1.34Å' scene=''> | <StructureSection load='4u3b' size='340' side='right' caption='[[4u3b]], [[Resolution|resolution]] 1.34Å' scene=''> | ||
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<table><tr><td colspan='2'>[[4u3b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U3B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U3B FirstGlance]. <br> | <table><tr><td colspan='2'>[[4u3b]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4U3B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4U3B FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3BW:4-({[4-(4-CHLOROPHENOXY)PHENYL]SULFANYL}METHYL)-N-HYDROXYTETRAHYDRO-2H-PYRAN-4-CARBOXAMIDE'>3BW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3BW:4-({[4-(4-CHLOROPHENOXY)PHENYL]SULFANYL}METHYL)-N-HYDROXYTETRAHYDRO-2H-PYRAN-4-CARBOXAMIDE'>3BW</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4u3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u3b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4u3b RCSB], [http://www.ebi.ac.uk/pdbsum/4u3b PDBsum]</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=4u3b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4u3b OCA], [http://pdbe.org/4u3b PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4u3b RCSB], [http://www.ebi.ac.uk/pdbsum/4u3b PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4u3b ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4u3b" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 11:33, 5 August 2016
LpxC from A.Aaeolicus in complex with the MMP inhibitor 4-[[4-(4-chlorophenoxy)phenyl]sulfanylmethyl]tetrahydropyran-4-carbohydroxamic acid - compound 2
Structural highlights
Function[LPXC_AQUAE] Involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell (By similarity). Publication Abstract from PubMedIn the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization. Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.,Murphy-Benenato KE, Olivier N, Choy A, Ross PL, Miller MD, Thresher J, Gao N, Hale MR ACS Med Chem Lett. 2014 Sep 23;5(11):1213-1218. eCollection 2014 Nov 13. PMID:25408833[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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