6wnk - Revision history

OCA at 14:31, 18 October 2023

2023-10-18T14:31:19Z

←Older revision		Revision as of 14:31, 18 October 2023
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-	====	+	==Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome==
-	<StructureSection load='6wnk' size='340' side='right'caption='[[6wnk]]' scene=''>	+	<StructureSection load='6wnk' size='340' side='right'caption='[[6wnk]], [[Resolution\|resolution]] 2.28Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6wnk]] is a 28 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WNK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WNK 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=6wnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wnk OCA], [https://pdbe.org/6wnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wnk RCSB], [https://www.ebi.ac.uk/pdbsum/6wnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wnk 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]] 2.28Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=U5Y:(12S,15S)-N-[(2-fluorophenyl)methyl]-10,13-dioxo-12-{2-oxo-2-[(2R)-2-phenylpyrrolidin-1-yl]ethyl}-2-oxa-11,14-diazatricyclo[15.2.2.1~3,7~]docosa-1(19),3(22),4,6,17,20-hexaene-15-carboxamide'>U5Y</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=6wnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wnk OCA], [https://pdbe.org/6wnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wnk RCSB], [https://www.ebi.ac.uk/pdbsum/6wnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wnk ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/PSA_MYCTU PSA_MYCTU] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues. Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins. One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice. The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated.<ref>PMID:16468985</ref> <ref>PMID:18059281</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Treatment of tuberculosis (TB) currently takes at least 6 months. Latent Mycobacterium tuberculosis (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle 6. The cocrystal structure of macrocycle 6 with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by 6 dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
		+
		+	Macrocyclic Peptides that Selectively Inhibit the Mycobacterium tuberculosis Proteasome.,Zhang H, Hsu HC, Kahne SC, Hara R, Zhan W, Jiang X, Burns-Huang K, Ouellette T, Imaeda T, Okamoto R, Kawasaki M, Michino M, Wong TT, Toita A, Yukawa T, Moraca F, Vendome J, Saha P, Sato K, Aso K, Ginn J, Meinke PT, Foley M, Nathan CF, Darwin KH, Li H, Lin G J Med Chem. 2021 May 13;64(9):6262-6272. doi: 10.1021/acs.jmedchem.1c00296. Epub , 2021 May 5. PMID:33949190<ref>PMID:33949190</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6wnk" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Proteasome 3D structures\|Proteasome 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Z-disk~~]]	+	[[Category: Mycobacterium tuberculosis]]
		+	[[Category: Hsu HC]]
		+	[[Category: Li H]]

OCA at 05:17, 28 April 2021

2021-04-28T05:17:46Z

←Older revision		Revision as of 05:17, 28 April 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 6wnk ~~is ON HOLD until Paper Publication~~	+	====
-		+	<StructureSection load='6wnk' size='340' side='right'caption='[[6wnk]]' scene=''>
-	~~Authors~~: ~~Hsu, H~~.C.~~, Li, H~~.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br>
-	~~Description: Macrocyclic peptides TDI5575 that selectively inhibit~~ the ~~Mycobacterium tuberculosis proteasome~~	+	</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=6wnk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wnk OCA], [https://pdbe.org/6wnk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wnk RCSB], [https://www.ebi.ac.uk/pdbsum/6wnk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wnk ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[Category: ~~Li, H~~]]	+	__TOC__
-	[[Category: ~~Hsu, H.C~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Z-disk]]

OCA at 04:43, 27 May 2020

2020-05-27T04:43:03Z

←Older revision		Revision as of 04:43, 27 May 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6wnk is ON HOLD	+	The entry 6wnk is ON HOLD until Paper Publication

	Authors: Hsu, H.C., Li, H.		Authors: Hsu, H.C., Li, H.
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	Description: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome		Description: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Hsu, H.C]]
	[[Category: Li, H]]		[[Category: Li, H]]
		+	[[Category: Hsu, H.C]]

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

2020-04-29T05:20:23Z

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

←Older revision

Revision as of 05:20, 29 April 2020

OCA: New page: '''Unreleased structure''' The entry 6wnk is ON HOLD Authors: Hsu, H.C., Li, H. Description: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis protea...

2020-04-29T05:20:22Z

New page: '''Unreleased structure''' The entry 6wnk is ON HOLD Authors: Hsu, H.C., Li, H. Description: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis protea...

New page

'''Unreleased structure'''

The entry 6wnk is ON HOLD

Authors: Hsu, H.C., Li, H.

Description: Macrocyclic peptides TDI5575 that selectively inhibit the Mycobacterium tuberculosis proteasome
[[Category: Unreleased Structures]]
[[Category: Hsu, H.C]]
[[Category: Li, H]]