7t33 - Revision history

OCA at 16:58, 18 October 2023

OCA — Wed, 18 Oct 2023 16:58:22 GMT

←Older revision		Revision as of 16:58, 18 October 2023
Line 1:		Line 1:

	==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==		==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==
-	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]]' scene=''>	+	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7t33]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Haemophilus_influenzae_Rd_KW20 Haemophilus influenzae Rd KW20]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>
-	</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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></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]] 2.301Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NIO:NICOTINIC+ACID'>NIO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/Y1278_HAEIN Y1278_HAEIN]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Nitroheterocycle antibiotics, particularly 5-nitroimidazoles, are frequently used for treating anaerobic infections. The antimicrobial activities of these drugs heavily rely on the in vivo bioactivation, mainly mediated by widely distributed bacterial nitroreductases (NTRs). However, the bioactivation can also lead to severe toxicities and drug resistance. Mechanistic understanding of NTR-mediated 5-nitroimidazole metabolism can potentially aid addressing these issues. Here, we report the metabolism of structurally diverse nitroimidazole drug molecules by a NTR from a human pathogen Haemophilus influenzae (HiNfsB). Our detailed bioinformatic analysis uncovered that HiNfsB represents a group of unexplored oxygen-insensitive NTRs. Biochemical characterization of the recombinant enzyme revealed that HiNfsB effectively metabolizes ten clinically used nitroimidazoles. Furthermore, HiNfsB generated not only canonical nitroreduction metabolites but also stable, novel dimeric products from three nitroimidazoles, whose structures were proposed based on the results of high resolution MS and tandem MS analysis. X-ray structural analysis of the enzyme coupled with site-directed mutagenesis identified four active site residues important to its catalysis and broad substrate scope. Finally, transient expression of HiNfsB sensitized an E. coli mutant strain to 5-nitroimidazoles under anaerobic conditions. Together, these results advance our understanding of the metabolism of nitroimidazole antibiotics mediated by a new NTR group and reinforce the research on the natural antibiotic resistome for addressing the antibiotic resistance crisis.
		+
		+	Biochemical and structural characterization of Haemophilus influenzae nitroreductase in metabolizing nitroimidazoles.,Liu D, Wanniarachchi TN, Jiang G, Seabra G, Cao S, Bruner SD, Ding Y RSC Chem Biol. 2022 Feb 16;3(4):436-446. doi: 10.1039/d1cb00238d. eCollection, 2022 Apr 6. PMID:35441146<ref>PMID:35441146</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7t33" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Haemophilus influenzae Rd KW20]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Bruner SD]]		[[Category: Bruner SD]]
	[[Category: Wanniarachchi TN]]		[[Category: Wanniarachchi TN]]

OCA at 14:50, 31 August 2022

OCA — Wed, 31 Aug 2022 14:50:06 GMT

←Older revision		Revision as of 14:50, 31 August 2022
Line 1:		Line 1:

	==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==		==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==
-	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]]~~, [[Resolution\|resolution]] 2.30Å~~' scene=''>	+	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]]' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>~~[[7t33]] is a 2 chain structure.~~ Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>	+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NIO:NICOTINIC+ACID'>NIO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>	+	</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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7t2z\|7t2z]]</div></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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>	+
	</table>		</table>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Nitroheterocycle antibiotics, particularly 5-nitroimidazoles, are frequently used for treating anaerobic infections. The antimicrobial activities of these drugs heavily rely on the in vivo bioactivation, mainly mediated by widely distributed bacterial nitroreductases (NTRs). However, the bioactivation can also lead to severe toxicities and drug resistance. Mechanistic understanding of NTR-mediated 5-nitroimidazole metabolism can potentially aid addressing these issues. Here, we report the metabolism of structurally diverse nitroimidazole drug molecules by a NTR from a human pathogen Haemophilus influenzae (HiNfsB). Our detailed bioinformatic analysis uncovered that HiNfsB represents a group of unexplored oxygen-insensitive NTRs. Biochemical characterization of the recombinant enzyme revealed that HiNfsB effectively metabolizes ten clinically used nitroimidazoles. Furthermore, HiNfsB generated not only canonical nitroreduction metabolites but also stable, novel dimeric products from three nitroimidazoles, whose structures were proposed based on the results of high resolution MS and tandem MS analysis. X-ray structural analysis of the enzyme coupled with site-directed mutagenesis identified four active site residues important to its catalysis and broad substrate scope. Finally, transient expression of HiNfsB sensitized an E. coli mutant strain to 5-nitroimidazoles under anaerobic conditions. Together, these results advance our understanding of the metabolism of nitroimidazole antibiotics mediated by a new NTR group and reinforce the research on the natural antibiotic resistome for addressing the antibiotic resistance crisis.
-
-	Biochemical and structural characterization of Haemophilus influenzae nitroreductase in metabolizing nitroimidazoles.,Liu D, Wanniarachchi TN, Jiang G, Seabra G, Cao S, Bruner SD, Ding Y RSC Chem Biol. 2022 Feb 16;3(4):436-446. doi: 10.1039/d1cb00238d. eCollection, 2022 Apr 6. PMID:35441146<ref>PMID:35441146</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 7t33" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bruner~~, S D~~]]	+	[[Category: Bruner SD]]
-	[[Category: Wanniarachchi~~, T N]]~~	+	[[Category: Wanniarachchi TN]]
-	~~[[Category: Nitroreductase haemophilus influenzae nicotinic acid]]~~	+
-	~~[[Category: Oxidoreductase~~]]	+

OCA at 06:33, 12 May 2022

OCA — Thu, 12 May 2022 06:33:31 GMT

←Older revision		Revision as of 06:33, 12 May 2022
Line 1:		Line 1:

	==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==		==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==
-	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]]' scene=''>	+	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7t33]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>
-	</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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NIO:NICOTINIC+ACID'>NIO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7t2z\|7t2z]]</div></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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Nitroheterocycle antibiotics, particularly 5-nitroimidazoles, are frequently used for treating anaerobic infections. The antimicrobial activities of these drugs heavily rely on the in vivo bioactivation, mainly mediated by widely distributed bacterial nitroreductases (NTRs). However, the bioactivation can also lead to severe toxicities and drug resistance. Mechanistic understanding of NTR-mediated 5-nitroimidazole metabolism can potentially aid addressing these issues. Here, we report the metabolism of structurally diverse nitroimidazole drug molecules by a NTR from a human pathogen Haemophilus influenzae (HiNfsB). Our detailed bioinformatic analysis uncovered that HiNfsB represents a group of unexplored oxygen-insensitive NTRs. Biochemical characterization of the recombinant enzyme revealed that HiNfsB effectively metabolizes ten clinically used nitroimidazoles. Furthermore, HiNfsB generated not only canonical nitroreduction metabolites but also stable, novel dimeric products from three nitroimidazoles, whose structures were proposed based on the results of high resolution MS and tandem MS analysis. X-ray structural analysis of the enzyme coupled with site-directed mutagenesis identified four active site residues important to its catalysis and broad substrate scope. Finally, transient expression of HiNfsB sensitized an E. coli mutant strain to 5-nitroimidazoles under anaerobic conditions. Together, these results advance our understanding of the metabolism of nitroimidazole antibiotics mediated by a new NTR group and reinforce the research on the natural antibiotic resistome for addressing the antibiotic resistance crisis.
		+
		+	Biochemical and structural characterization of Haemophilus influenzae nitroreductase in metabolizing nitroimidazoles.,Liu D, Wanniarachchi TN, Jiang G, Seabra G, Cao S, Bruner SD, Ding Y RSC Chem Biol. 2022 Feb 16;3(4):436-446. doi: 10.1039/d1cb00238d. eCollection, 2022 Apr 6. PMID:35441146<ref>PMID:35441146</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7t33" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bruner SD]]	+	[[Category: Bruner, S D]]
-	[[Category: Wanniarachchi TN]]	+	[[Category: Wanniarachchi, T N]]
		+	[[Category: Nitroreductase haemophilus influenzae nicotinic acid]]
		+	[[Category: Oxidoreductase]]

OCA at 07:44, 23 February 2022

OCA — Wed, 23 Feb 2022 07:44:24 GMT

←Older revision		Revision as of 07:44, 23 February 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The ~~entry~~ 7t33 ~~is ON HOLD until Paper Publication~~	+	==The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid==
-		+	<StructureSection load='7t33' size='340' side='right'caption='[[7t33]]' scene=''>
-	~~Authors~~: ~~Wanniarachchi~~, T.N., ~~Bruner~~, S.D.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T33 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T33 FirstGlance]. <br>
-	~~Description: The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid~~	+	</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=7t33 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t33 OCA], [https://pdbe.org/7t33 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t33 RCSB], [https://www.ebi.ac.uk/pdbsum/7t33 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t33 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Wanniarachchi, T.N~~]]	+	__TOC__
-	[[Category: ~~Bruner, S.D~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Bruner SD]]
		+	[[Category: Wanniarachchi TN]]

OCA: Protected "7t33" [edit=sysop:move=sysop]

OCA — Wed, 15 Dec 2021 15:43:09 GMT

Protected "7t33" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:43, 15 December 2021

OCA: New page: '''Unreleased structure''' The entry 7t33 is ON HOLD until Paper Publication Authors: Wanniarachchi, T.N., Bruner, S.D. Description: The structure of Haemophilus influenzae Rd KW20 nit...

OCA — Wed, 15 Dec 2021 15:43:08 GMT

New page: '''Unreleased structure''' The entry 7t33 is ON HOLD until Paper Publication Authors: Wanniarachchi, T.N., Bruner, S.D. Description: The structure of Haemophilus influenzae Rd KW20 nit...

New page

'''Unreleased structure'''

The entry 7t33 is ON HOLD until Paper Publication

Authors: Wanniarachchi, T.N., Bruner, S.D.

Description: The structure of Haemophilus influenzae Rd KW20 nitroreductase complexed with nicotinic acid
[[Category: Unreleased Structures]]
[[Category: Wanniarachchi, T.N]]
[[Category: Bruner, S.D]]