6moo
From Proteopedia
(Difference between revisions)
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<StructureSection load='6moo' size='340' side='right'caption='[[6moo]], [[Resolution|resolution]] 2.20Å' scene=''> | <StructureSection load='6moo' size='340' side='right'caption='[[6moo]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6moo]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6moo]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MOO FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A5F:N-[(2S)-3-azanyl-3-methyl-1-(oxidanylamino)-1-oxidanylidene-butan-2-yl]-4-[4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide'>A5F</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=A5F:N-[(2S)-3-azanyl-3-methyl-1-(oxidanylamino)-1-oxidanylidene-butan-2-yl]-4-[4-[(1R,2R)-2-(hydroxymethyl)cyclopropyl]buta-1,3-diynyl]benzamide'>A5F</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">lpxC_1, lpxC, C0044_32665, C8257_27020, CAZ10_21290, CGU42_01150, CW299_32585, DI492_11215, DN070_30465, DT376_11200, NCTC13719_04761, PAERUG_E15_London_28_01_14_00522, RW109_RW109_05745 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-3-O-acyl-N-acetylglucosamine_deacetylase UDP-3-O-acyl-N-acetylglucosamine deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.108 3.5.1.108] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/UDP-3-O-acyl-N-acetylglucosamine_deacetylase UDP-3-O-acyl-N-acetylglucosamine deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.108 3.5.1.108] </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=6moo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6moo OCA], [http://pdbe.org/6moo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6moo RCSB], [http://www.ebi.ac.uk/pdbsum/6moo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6moo ProSAT]</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=6moo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6moo OCA], [http://pdbe.org/6moo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6moo RCSB], [http://www.ebi.ac.uk/pdbsum/6moo PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6moo ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/A0A072ZC86_PSEAI A0A072ZC86_PSEAI]] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.[HAMAP-Rule:MF_00388][SAAS:SAAS00531485] | [[http://www.uniprot.org/uniprot/A0A072ZC86_PSEAI A0A072ZC86_PSEAI]] Catalyzes the hydrolysis of UDP-3-O-myristoyl-N-acetylglucosamine to form UDP-3-O-myristoylglucosamine and acetate, the committed step in lipid A biosynthesis.[HAMAP-Rule:MF_00388][SAAS:SAAS00531485] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | LpxC is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram(-) bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxy methyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. We report here the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on overall profile, 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hy droxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided solubility of >30 mg/mL for parenteral administration and conversion to the active drug with a T1/2 of approximately 2 minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development. | ||
| + | |||
| + | -Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.,Cohen F, Aggen JB, Andrews LD, Assar Z, Boggs J, Choi T, Dozzo P, Easterday AN, Haglund CM, Hildebrandt DJ, Holt MC, Joly K, Jubb A, Kamal Z, Kane TR, Konradi AW, Krause KM, Linsell MS, Machajewski TD, Miroshnikova O, Moser HE, Nieto V, Phan T, Plato C, Serio AW, Seroogy J, Shakhmin A, Stein AJ, Sun AD, Sviridov S, Wang Z, Wlasichuk K, Yang W, Zhou X, Zhu H, Cirz RT ChemMedChem. 2019 Jul 8. doi: 10.1002/cmdc.201900287. PMID:31283109<ref>PMID:31283109</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6moo" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 08:38, 24 July 2019
Co-Crystal structure of P. aeruginosa LpxC-achn975 complex
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