OCA at 06:21, 28 September 2022

OCA — Wed, 28 Sep 2022 06:21:54 GMT

←Older revision		Revision as of 06:21, 28 September 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7zyj is ~~ON HOLD until Paper~~ Publication	+	==Leishmania tarentolae proteasome 20S subunit in complex with compound 2==
		+	<StructureSection load='7zyj' size='340' side='right'caption='[[7zyj]], [[Resolution\|resolution]] 2.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[7zyj]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_tarentolae Leishmania tarentolae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZYJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZYJ FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KFC:~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide'>KFC</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=7zyj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zyj OCA], [https://pdbe.org/7zyj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zyj RCSB], [https://www.ebi.ac.uk/pdbsum/7zyj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zyj ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/A0A640KBV2_LEITA A0A640KBV2_LEITA]] The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.[RuleBase:RU000551]
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.

-	~~Authors: Srinivas~~, H.	+	Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT).,Koester DC, Marx VM, Williams S, Jiricek J, Dauphinais M, Rene O, Miller SL, Zhang L, Patra D, Chen YL, Cheung H, Gable J, Lakshminarayana SB, Osborne C, Galarneau JR, Kulkarni U, Richmond W, Bretz A, Xiao L, Supek F, Wiesmann C, Honnappa S, Be C, Maser P, Kaiser M, Ritchie R, Barrett MP, Diagana TT, Sarko C, Rao SPS J Med Chem. 2022 Sep 8;65(17):11776-11787. doi: 10.1021/acs.jmedchem.2c00791., Epub 2022 Aug 22. PMID:35993839<ref>PMID:35993839</ref>

-	~~Description~~: ~~Leishmania tarentolae proteasome 20S subunit in complex with compound 2~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Srinivas, H]]	+	<div class="pdbe-citations 7zyj" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Leishmania tarentolae]]
		+	[[Category: Srinivas H]]

OCA at 06:18, 29 June 2022

OCA — Wed, 29 Jun 2022 06:18:01 GMT

←Older revision		Revision as of 06:18, 29 June 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7zyj is ON HOLD	+	The entry 7zyj is ON HOLD until Paper Publication

	Authors: Srinivas, H.		Authors: Srinivas, H.

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

OCA — Wed, 08 Jun 2022 04:18:07 GMT

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

←Older revision

Revision as of 04:18, 8 June 2022

OCA: New page: '''Unreleased structure''' The entry 7zyj is ON HOLD Authors: Srinivas, H. Description: Leishmania tarentolae proteasome 20S subunit in complex with compound 2 [[Category: Unreleased S...

OCA — Wed, 08 Jun 2022 04:18:06 GMT

New page: '''Unreleased structure''' The entry 7zyj is ON HOLD Authors: Srinivas, H. Description: Leishmania tarentolae proteasome 20S subunit in complex with compound 2 [[Category: Unreleased S...

New page

'''Unreleased structure'''

The entry 7zyj is ON HOLD

Authors: Srinivas, H.

Description: Leishmania tarentolae proteasome 20S subunit in complex with compound 2
[[Category: Unreleased Structures]]
[[Category: Srinivas, H]]

7zyj - Revision history

OCA at 06:21, 28 September 2022

OCA at 06:18, 29 June 2022

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

OCA: New page: '''Unreleased structure''' The entry 7zyj is ON HOLD Authors: Srinivas, H. Description: Leishmania tarentolae proteasome 20S subunit in complex with compound 2 [[Category: Unreleased S...