6ro2 - Revision history

OCA at 10:25, 23 October 2024

2024-10-23T10:25:55Z

← Older revision		Revision as of 10:25, 23 October 2024
Line 3:		Line 3:
	<StructureSection load='6ro2' size='340' side='right'caption='[[6ro2]], [[Resolution\|resolution]] 1.82Å' scene=''>		<StructureSection load='6ro2' size='340' side='right'caption='[[6ro2]], [[Resolution\|resolution]] 1.82Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6ro2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Lactococcus_cremoris Lactococcus cremoris] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RO2 FirstGlance]. <br>		<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RO2 FirstGlance]. <br>
	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.821Å</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]] 1.821Å</td></tr>
	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2ON:2-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>2ON</scene>, <scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2ON:2-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>2ON</scene>, <scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6ro2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ro2 OCA], [https://pdbe.org/6ro2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ro2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ro2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ro2 ProSAT]</span></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=6ro2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ro2 OCA], [https://pdbe.org/6ro2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ro2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ro2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ro2 ProSAT]</span></td></tr>
	</table>		</table>
	== ~~Function~~ ==		<div style="background-color:#fffaf0;">
	~~[https://www~~.~~uniprot~~.~~org/uniprot~~/~~FPG_LACLC FPG_LACLC] Involved in base excision repair of~~ DNA ~~damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes~~ and ~~removes damaged bases. Has~~ a ~~preference for oxidized purines, such as 7,8~~-~~dihydro~~-~~8-oxoguanine~~ (~~8-oxoG~~). ~~Has AP~~ (~~apurinic/apyrimidinic~~) ~~lyase activity~~ and ~~introduces nicks in the~~ DNA ~~strand~~. ~~Cleaves the DNA backbone by beta~~-~~delta elimination~~ to ~~generate a single-strand break~~ at the ~~site~~ of the ~~removed base with both 3'~~- and 5'-~~phosphates~~.<ref>PMID:~~7704272~~</ref>		== Publication Abstract from PubMed ==
			DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

			Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.,Rieux C, Goffinont S, Coste F, Tber Z, Cros J, Roy V, Guerin M, Gaudon V, Bourg S, Biela A, Aucagne V, Agrofoglio L, Garnier N, Castaing B Int J Mol Sci. 2020 Mar 17;21(6). pii: ijms21062058. doi: 10.3390/ijms21062058. PMID:32192183<ref>PMID:32192183</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 6ro2" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 17:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	~~[[Category: Lactococcus cremoris]]~~
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Synthetic construct]]~~
	[[Category: Castaing B]]		[[Category: Castaing B]]
	[[Category: Coste F]]		[[Category: Coste F]]
	[[Category: Goffinont S]]		[[Category: Goffinont S]]

OCA at 07:49, 7 February 2024

2024-02-07T07:49:41Z

← Older revision		Revision as of 07:49, 7 February 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/FPG_LACLC FPG_LACLC] Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.<ref>PMID:7704272</ref>		[https://www.uniprot.org/uniprot/FPG_LACLC FPG_LACLC] Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.<ref>PMID:7704272</ref>
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

	Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.,Rieux C, Goffinont S, Coste F, Tber Z, Cros J, Roy V, Guerin M, Gaudon V, Bourg S, Biela A, Aucagne V, Agrofoglio L, Garnier N, Castaing B Int J Mol Sci. 2020 Mar 17;21(6). pii: ijms21062058. doi: 10.3390/ijms21062058. PMID:32192183<ref>PMID:32192183</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 6ro2" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==

OCA at 06:17, 19 July 2023

2023-07-19T06:17:21Z

← Older revision		Revision as of 06:17, 19 July 2023
Line 1:		Line 1:

	==The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor==		==The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor==
	<StructureSection load='6ro2' size='340' side='right'caption='[[6ro2]]' scene=''>		<StructureSection load='6ro2' size='340' side='right'caption='[[6ro2]], [[Resolution\|resolution]] 1.82Å' 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=6RO2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6RO2 FirstGlance]. <br>		<table><tr><td colspan='2'>[[6ro2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Lactococcus_cremoris Lactococcus cremoris] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RO2 FirstGlance]. <br>
	</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=6ro2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ro2 OCA], [~~http~~://pdbe.org/6ro2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6ro2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6ro2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6ro2 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]] 1.821Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2ON:2-SULFANYL-1,9-DIHYDRO-6H-PURIN-6-ONE'>2ON</scene>, <scene name='pdbligand=3DR:1,2-DIDEOXYRIBOFURANOSE-5-PHOSPHATE'>3DR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6ro2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ro2 OCA], [https://pdbe.org/6ro2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ro2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ro2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ro2 ProSAT]</span></td></tr>
	</table>		</table>
			== Function ==
			[https://www.uniprot.org/uniprot/FPG_LACLC FPG_LACLC] Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG). Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates.<ref>PMID:7704272</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

			Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights.,Rieux C, Goffinont S, Coste F, Tber Z, Cros J, Roy V, Guerin M, Gaudon V, Bourg S, Biela A, Aucagne V, Agrofoglio L, Garnier N, Castaing B Int J Mol Sci. 2020 Mar 17;21(6). pii: ijms21062058. doi: 10.3390/ijms21062058. PMID:32192183<ref>PMID:32192183</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 6ro2" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[DNA glycosylase 3D structures\|DNA glycosylase 3D structures]]
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Lactococcus cremoris]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
			[[Category: Synthetic construct]]
	[[Category: Castaing B]]		[[Category: Castaing B]]
	[[Category: Coste F]]		[[Category: Coste F]]
	[[Category: Goffinont S]]		[[Category: Goffinont S]]

OCA at 06:57, 15 April 2020

2020-04-15T06:57:24Z

← Older revision		Revision as of 06:57, 15 April 2020
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry 6ro2 is ON HOLD until Paper Publication~~		==The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor==
			<StructureSection load='6ro2' size='340' side='right'caption='[[6ro2]]' scene=''>
	~~Authors: Coste, F., Goffinont, S., Castaing, B.~~		== Structural highlights ==
			<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RO2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RO2 FirstGlance]. <br>
	~~Description:~~ The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor		</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=6ro2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ro2 OCA], [http://pdbe.org/6ro2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ro2 RCSB], [http://www.ebi.ac.uk/pdbsum/6ro2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ro2 ProSAT]</span></td></tr>
	[[Category: ~~Unreleased~~ Structures]]		</table>
	[[Category: Castaing, B]]		__TOC__
	[[Category: Coste, F]]		</StructureSection>
	[[Category: Goffinont, S]]		[[Category: Large Structures]]
			[[Category: Castaing B]]
			[[Category: Coste F]]
			[[Category: Goffinont S]]

OCA: Protected "6ro2" [edit=sysop:move=sysop]

2019-05-22T04:14:57Z

Protected "6ro2" [edit=sysop:move=sysop]

← Older revision	Revision as of 04:14, 22 May 2019
(No difference)

OCA: New page: '''Unreleased structure''' The entry 6ro2 is ON HOLD until Paper Publication Authors: Coste, F., Goffinont, S., Castaing, B. Description: The crystal structure of a complex between the...

2019-05-22T04:14:56Z

New page: '''Unreleased structure''' The entry 6ro2 is ON HOLD until Paper Publication Authors: Coste, F., Goffinont, S., Castaing, B. Description: The crystal structure of a complex between the...

New page

'''Unreleased structure'''

The entry 6ro2 is ON HOLD until Paper Publication

Authors: Coste, F., Goffinont, S., Castaing, B.

Description: The crystal structure of a complex between the LlFpg protein, a THF-DNA and an inhibitor
[[Category: Unreleased Structures]]
[[Category: Castaing, B]]
[[Category: Coste, F]]
[[Category: Goffinont, S]]