6p86

From Proteopedia

(Difference between revisions)

Revision as of 06:57, 25 June 2020

E.coli LpxD in complex with compound 4.1

Structural highlights

6p86 is a 3 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	lpxD, lpxD_1, lpxD_2, A8C65_17800, A9R57_04450, AC789_1c01770, ACN002_0184, ACN77_17005, ACN81_28485, ACU57_18525, ACU90_26495, AM270_18210, AML07_22885, AML35_22825, APZ14_11060, AUQ13_07450, AUS26_23195, AW059_09890, AW106_08805, B1K96_12940, B7C53_01310, BANRA_00558, BANRA_00653, BANRA_02262, BANRA_03350, BET08_19125, BHF46_07835, BHS81_00700, BHS87_00855, BIZ41_19025, BJJ90_21310, BK292_13720, BK400_03560, BMT53_09465, BN17_46021, BTQ06_06540, BUE81_01655, BVL39_02135, BW690_02415, BZL31_14885, C2U48_09555, C4J69_03380, C5N07_08630, C5P01_08975, C5P43_07335, C6669_04195, C6986_01145, C7235_20180, C7B06_05915, C7B07_04225, CA593_02815, CG691_14440, CG692_09445, CG705_12975, CG706_12690, COD30_14715, COD46_06685, CR538_20590, CR539_04985, CRM83_15040, CXB56_23080, D0X26_09365, D2184_08545, D2185_20180, D2F89_01460, D3821_06260, D3O91_03240, D3Y67_16455, D9D20_18680, D9D55_03030, D9D69_06830, D9E22_13300, D9E35_14480, D9G42_07535, D9H66_18155, D9H68_13825, D9I18_15010, D9I87_01590, D9I97_03755, D9J11_16875, D9J44_14030, DIV22_06320, DL545_20340, DMZ31_06810, DNQ41_04690, DNQ45_10065, DQF57_05615, DQO13_06200, DS732_05825, DTL43_05870, EAI42_08350, EAI46_03595, EAI52_11055, EC1094V2_3672, EC3234A_2c01610, EC3426_00931, EC382_03005, ECTO6_03883, ED287_04550, ED600_04595, EEP23_00115, EFV01_09910, EFV02_20465, EFV04_15215, EFV08_17150, EFV11_08135, EFV12_18845, EFV15_17225, EFV17_09875, EIA13_13600, EL75_3585, EL79_3695, EL80_3642, ERS085374_03841, ERS150873_01122, ERS150876_00054, FORC28_5013, HW43_04650, JD73_13090, NCTC10429_04183, NCTC10865_05054, NCTC11022_04906, NCTC11126_03647, NCTC13462_02218, NCTC8500_04533, NCTC8960_01551, NCTC9037_04178, NCTC9045_04699, NCTC9055_00956, NCTC9058_02808, NCTC9062_04225, NCTC9706_01326, NCTC9969_04255, PU06_22990, RG28_03860, RK56_027945, RX35_04913, SAMEA3472043_02537, SAMEA3472044_04146, SAMEA3472047_02509, SAMEA3472070_02384, SAMEA3472080_03763, SAMEA3472114_03609, SAMEA3484427_01386, SAMEA3484429_01095, SAMEA3752553_02884, SAMEA3752557_00885, SAMEA3752559_03701, SAMEA3753064_03381, SAMEA3753097_03916, SAMEA3753290_00404, SAMEA3753300_01852, SK85_00179, WQ89_09605, WR15_02380 ("Bacillus coli" Migula 1895)
Activity:	UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase, with EC number 2.3.1.191
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[Q0P6M7_ECOLX] Catalyzes the N-acylation of UDP-3-O-(hydroxytetradecanoyl)glucosamine using 3-hydroxytetradecanoyl-ACP as the acyl donor. Is involved in the biosynthesis of lipid A, a phosphorylated glycolipid that anchors the lipopolysaccharide to the outer membrane of the cell.[HAMAP-Rule:MF_00523]

Publication Abstract from PubMed

LpxD, acyl-ACP-dependent N-acyltransferase, is the third enzyme of lipid A biosynthesis in Gram-negative bacteria. A recent probe-based screen identified several compounds, including 6359-0284 (compound 1), that inhibit the enzymatic activity of Escherichia coli (E. coli) LpxD. Here, we use these inhibitors to chemically validate LpxD as an attractive antibacterial target. We first found that compound 1 was oxidized in solution to the more stable aromatized tetrahydro-pyrazolo-quinolinone compound 1o. From the Escherichia coli strain deficient in efflux, we isolated a mutant that was less susceptible to compound 1o and had an lpxD missense mutation (Gly268Cys), supporting the cellular on-target activity. Using surface plasma resonance, we showed direct binding to E. coli LpxD for compound 1o and other reported LpxD inhibitors in vitro. Furthermore, we determined eight cocrystal structures of E. coli LpxD/inhibitor complexes. These costructures pinpointed the 4'-phosphopantetheine binding site as the common ligand binding hotspot, where hydrogen bonds to Gly269 and/or Gly287 were important for inhibitor binding. In addition, the LpxD/compound 1o costructure rationalized the reduced activity of compound 1o in the LpxDGly268Cys mutant. Moreover, we obtained the LpxD structure in complex with a previously reported LpxA/LpxD dual targeting peptide inhibitor, RJPXD33, providing structural rationale for the unique dual targeting properties of this peptide. Given that the active site residues of LpxD are conserved in multidrug resistant Enterobacteriaceae, this work paves the way for future LpxD drug discovery efforts combating these Gram-negative pathogens.

Structural and Biological Basis of Small Molecule Inhibition of Escherichia coli LpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis.,Ma X, Prathapam R, Wartchow C, Chie-Leon B, Ho CM, De Vicente J, Han W, Li M, Lu Y, Ramurthy S, Shia S, Steffek M, Uehara T ACS Infect Dis. 2019 Aug 22. doi: 10.1021/acsinfecdis.9b00127. PMID:31402665^[1]

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

References

↑ Ma X, Prathapam R, Wartchow C, Chie-Leon B, Ho CM, De Vicente J, Han W, Li M, Lu Y, Ramurthy S, Shia S, Steffek M, Uehara T. Structural and Biological Basis of Small Molecule Inhibition of Escherichia coli LpxD Acyltransferase Essential for Lipopolysaccharide Biosynthesis. ACS Infect Dis. 2019 Aug 22. doi: 10.1021/acsinfecdis.9b00127. PMID:31402665 doi:http://dx.doi.org/10.1021/acsinfecdis.9b00127

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6p86"

@@ Line 3: / Line 3: @@
 <StructureSection load='6p86' size='340' side='right'caption='[[6p86]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6p86]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P86 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6P86 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6p86]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6P86 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6P86 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O3V:3-hydroxy-7,7-dimethyl-2-phenyl-4-(thiophen-2-yl)-2,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one'>O3V</scene>, <scene name='pdbligand=O4S:N-[(4-ethylphenyl)methyl]-2-[(6aR)-6-oxo-3-(pyrrolidine-1-carbonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-5-yl]acetamide'>O4S</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O3V:3-hydroxy-7,7-dimethyl-2-phenyl-4-(thiophen-2-yl)-2,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one'>O3V</scene>, <scene name='pdbligand=O4S:N-[(4-ethylphenyl)methyl]-2-[(6aR)-6-oxo-3-(pyrrolidine-1-carbonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,2-a]quinoxalin-5-yl]acetamide'>O4S</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lpxD, lpxD_1, lpxD_2, A8C65_17800, A9R57_04450, AC789_1c01770, ACN002_0184, ACN77_17005, ACN81_28485, ACU57_18525, ACU90_26495, AM270_18210, AML07_22885, AML35_22825, APZ14_11060, AUQ13_07450, AUS26_23195, AW059_09890, AW106_08805, B1K96_12940, B7C53_01310, BANRA_00558, BANRA_00653, BANRA_02262, BANRA_03350, BET08_19125, BHF46_07835, BHS81_00700, BHS87_00855, BIZ41_19025, BJJ90_21310, BK292_13720, BK400_03560, BMT53_09465, BN17_46021, BTQ06_06540, BUE81_01655, BVL39_02135, BW690_02415, BZL31_14885, C2U48_09555, C4J69_03380, C5N07_08630, C5P01_08975, C5P43_07335, C6669_04195, C6986_01145, C7235_20180, C7B06_05915, C7B07_04225, CA593_02815, CG691_14440, CG692_09445, CG705_12975, CG706_12690, COD30_14715, COD46_06685, CR538_20590, CR539_04985, CRM83_15040, CXB56_23080, D0X26_09365, D2184_08545, D2185_20180, D2F89_01460, D3821_06260, D3O91_03240, D3Y67_16455, D9D20_18680, D9D55_03030, D9D69_06830, D9E22_13300, D9E35_14480, D9G42_07535, D9H66_18155, D9H68_13825, D9I18_15010, D9I87_01590, D9I97_03755, D9J11_16875, D9J44_14030, DIV22_06320, DL545_20340, DMZ31_06810, DNQ41_04690, DNQ45_10065, DQF57_05615, DQO13_06200, DS732_05825, DTL43_05870, EAI42_08350, EAI46_03595, EAI52_11055, EC1094V2_3672, EC3234A_2c01610, EC3426_00931, EC382_03005, ECTO6_03883, ED287_04550, ED600_04595, EEP23_00115, EFV01_09910, EFV02_20465, EFV04_15215, EFV08_17150, EFV11_08135, EFV12_18845, EFV15_17225, EFV17_09875, EIA13_13600, EL75_3585, EL79_3695, EL80_3642, ERS085374_03841, ERS150873_01122, ERS150876_00054, FORC28_5013, HW43_04650, JD73_13090, NCTC10429_04183, NCTC10865_05054, NCTC11022_04906, NCTC11126_03647, NCTC13462_02218, NCTC8500_04533, NCTC8960_01551, NCTC9037_04178, NCTC9045_04699, NCTC9055_00956, NCTC9058_02808, NCTC9062_04225, NCTC9706_01326, NCTC9969_04255, PU06_22990, RG28_03860, RK56_027945, RX35_04913, SAMEA3472043_02537, SAMEA3472044_04146, SAMEA3472047_02509, SAMEA3472070_02384, SAMEA3472080_03763, SAMEA3472114_03609, SAMEA3484427_01386, SAMEA3484429_01095, SAMEA3752553_02884, SAMEA3752557_00885, SAMEA3752559_03701, SAMEA3753064_03381, SAMEA3753097_03916, SAMEA3753290_00404, SAMEA3753300_01852, SK85_00179, WQ89_09605, WR15_02380 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</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-(3-hydroxymyristoyl)glucosamine_N-acyltransferase UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.191 2.3.1.191] </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=6p86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p86 OCA], [http://pdbe.org/6p86 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p86 RCSB], [http://www.ebi.ac.uk/pdbsum/6p86 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p86 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6p86 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6p86 OCA], [http://pdbe.org/6p86 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6p86 RCSB], [http://www.ebi.ac.uk/pdbsum/6p86 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6p86 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Bacillus coli migula 1895]]
 [[Category: Large Structures]]
 [[Category: Ma, X]]

6p86

From Proteopedia

Revision as of 06:57, 25 June 2020

E.coli LpxD in complex with compound 4.1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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