OCA at 11:47, 1 February 2024

2024-02-01T11:47:03Z

←Older revision		Revision as of 11:47, 1 February 2024
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8u7l is ~~ON HOLD~~	+	==Cryo-EM structure of LRRK2 bound to type II inhibitor GZD824==
		+	<StructureSection load='8u7l' size='340' side='right'caption='[[8u7l]], [[Resolution\|resolution]] 3.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8u7l]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8U7L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8U7L FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 3.6Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=T3X:4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide'>T3X</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=8u7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8u7l OCA], [https://pdbe.org/8u7l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8u7l RCSB], [https://www.ebi.ac.uk/pdbsum/8u7l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8u7l ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN] Defects in LRRK2 are the cause of Parkinson disease type 8 (PARK8) [MIM:[https://omim.org/entry/607060 607060]. A slowly progressive neurodegenerative disorder characterized by bradykinesia, rigidity, resting tremor, postural instability, neuronal loss in the substantia nigra, and the presence of neurofibrillary MAPT (tau)-positive and Lewy bodies in some patients.<ref>PMID:21850687</ref> <ref>PMID:16321986</ref> <ref>PMID:16269541</ref> <ref>PMID:15541309</ref> <ref>PMID:15541308</ref> <ref>PMID:16081470</ref> <ref>PMID:16087219</ref> <ref>PMID:15726496</ref> <ref>PMID:15732108</ref> <ref>PMID:15852371</ref> <ref>PMID:16240353</ref> <ref>PMID:15880653</ref> <ref>PMID:15929036</ref> <ref>PMID:16251215</ref> <ref>PMID:16272164</ref> <ref>PMID:16333314</ref> <ref>PMID:16272257</ref> <ref>PMID:15680455</ref> <ref>PMID:15680456</ref> <ref>PMID:15680457</ref> <ref>PMID:15811454</ref> <ref>PMID:16250030</ref> <ref>PMID:16172858</ref> <ref>PMID:16157901</ref> <ref>PMID:16247070</ref> <ref>PMID:16157908</ref> <ref>PMID:16157909</ref> <ref>PMID:15925109</ref> <ref>PMID:16298482</ref> <ref>PMID:16102999</ref> <ref>PMID:16533964</ref> <ref>PMID:17019612</ref> <ref>PMID:18213618</ref> <ref>PMID:21641266</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/LRRK2_HUMAN LRRK2_HUMAN] May play a role in the phosphorylation of proteins central to Parkinson disease. Phosphorylates PRDX3. May also have GTPase activity. Positively regulates autophagy through a calcium-dependent activation of the CaMKK/AMPK signaling pathway. The process involves activation of nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, increase in lysosomal pH, and calcium release from lysosomes.<ref>PMID:16352719</ref> <ref>PMID:20949042</ref> <ref>PMID:21850687</ref> <ref>PMID:22012985</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

-	~~Authors: Zhu~~, H., ~~Sun~~, J.	+	Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.,Zhu H, Hixson P, Ma W, Sun J Cell Discov. 2024 Jan 23;10(1):10. doi: 10.1038/s41421-023-00639-8. PMID:38263358<ref>PMID:38263358</ref>

-	~~Description: Cryo-EM structure~~ of ~~LRRK2 bound to type II inhibitor GZD824~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Zhu, H~~]]	+	<div class="pdbe-citations 8u7l" style="background-color:#fffaf0;"></div>
-	[[Category: Sun, J]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Sun J]]
		+	[[Category: Zhu H]]

OCA at 22:11, 27 December 2023

2023-12-27T22:11:38Z

←Older revision		Revision as of 22:11, 27 December 2023
Line 5:		Line 5:
	Authors: Zhu, H., Sun, J.		Authors: Zhu, H., Sun, J.

-	Description: Cryo-EM structure of LRRK2 bound to type II inhibitor ~~GZD-824~~	+	Description: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD824
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Zhu, H]]		[[Category: Zhu, H]]
	[[Category: Sun, J]]		[[Category: Sun, J]]

OCA: Protected "8u7l" [edit=sysop:move=sysop]

2023-09-27T05:09:04Z

Protected "8u7l" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:09, 27 September 2023

OCA: New page: '''Unreleased structure''' The entry 8u7l is ON HOLD Authors: Zhu, H., Sun, J. Description: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD-824 [[Category: Unreleased Structu...

2023-09-27T05:09:03Z

New page: '''Unreleased structure''' The entry 8u7l is ON HOLD Authors: Zhu, H., Sun, J. Description: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD-824 [[Category: Unreleased Structu...

New page

'''Unreleased structure'''

The entry 8u7l is ON HOLD

Authors: Zhu, H., Sun, J.

Description: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD-824
[[Category: Unreleased Structures]]
[[Category: Zhu, H]]
[[Category: Sun, J]]

8u7l - Revision history

OCA at 11:47, 1 February 2024

OCA at 22:11, 27 December 2023

OCA: Protected "8u7l" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8u7l is ON HOLD Authors: Zhu, H., Sun, J. Description: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD-824 [[Category: Unreleased Structu...