8im2 - Revision history

OCA at 14:08, 18 October 2023

OCA — Wed, 18 Oct 2023 14:08:32 GMT

←Older revision		Revision as of 14:08, 18 October 2023
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-	'''Unreleased structure'''

-	~~The entry~~ 8im2 is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of human HPPD complexed with NTBC==
		+	<StructureSection load='8im2' size='340' side='right'caption='[[8im2]], [[Resolution\|resolution]] 2.81Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8im2]] is a 6 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=8IM2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8IM2 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]] 2.81Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO:COBALT+(II)+ION'>CO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=NTD:2-{HYDROXY[2-NITRO-4-(TRIFLUOROMETHYL)PHENYL]METHYLENE}CYCLOHEXANE-1,3-DIONE'>NTD</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=8im2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8im2 OCA], [https://pdbe.org/8im2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8im2 RCSB], [https://www.ebi.ac.uk/pdbsum/8im2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8im2 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/HPPD_HUMAN HPPD_HUMAN] Defects in HPD are the cause of tyrosinemia type 3 (TYRO3) [MIM:[https://omim.org/entry/276710 276710]. TYRO3 is an inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation.<ref>PMID:10942115</ref> <ref>PMID:11073718</ref> Defects in HPD are a cause of hawkinsinuria (HAWK) [MIM:[https://omim.org/entry/140350 140350]. HAWK is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine.<ref>PMID:11073718</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/HPPD_HUMAN HPPD_HUMAN] Key enzyme in the degradation of tyrosine.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and alpha7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.

-	~~Authors: Dong~~, J~~., Lin~~, H~~.-Y.~~, Yang, G.-F.	+	Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.,Dong J, Xiao H, Chen JN, Zheng BF, Xu YL, Chen MX, Yang WC, Lin HY, Yang GF Structure. 2023 Sep 21:S0969-2126(23)00328-3. doi: 10.1016/j.str.2023.09.005. PMID:37794595<ref>PMID:37794595</ref>

-	~~Description: Crystal structure~~ of ~~human HPPD complexed with NTBC~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Lin, H.-Y~~]]	+	<div class="pdbe-citations 8im2" style="background-color:#fffaf0;"></div>
-	[[Category: Dong, J]]	+	== References ==
-	[[Category: Yang, G.-F]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Dong J]]
		+	[[Category: Lin H-Y]]
		+	[[Category: Yang G-F]]

OCA at 04:32, 23 August 2023

OCA — Wed, 23 Aug 2023 04:32:29 GMT

←Older revision		Revision as of 04:32, 23 August 2023
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8im2 is ON HOLD	+	The entry 8im2 is ON HOLD until Paper Publication

	Authors: Dong, J., Lin, H.-Y., Yang, G.-F.		Authors: Dong, J., Lin, H.-Y., Yang, G.-F.
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	Description: Crystal structure of human HPPD complexed with NTBC		Description: Crystal structure of human HPPD complexed with NTBC
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Yang, G.-F]]
	[[Category: Lin, H.-Y]]		[[Category: Lin, H.-Y]]
	[[Category: Dong, J]]		[[Category: Dong, J]]
		+	[[Category: Yang, G.-F]]

OCA at 03:48, 9 August 2023

OCA — Wed, 09 Aug 2023 03:48:29 GMT

←Older revision		Revision as of 03:48, 9 August 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8im2 is ON HOLD ~~until Paper Publication~~	+	The entry 8im2 is ON HOLD

-	Authors: Dong, J., ~~Yang~~, G.-F., ~~Lin~~, H.-Y.	+	Authors: Dong, J., Lin, H.-Y., Yang, G.-F.

-	Description: Crystal structure of human HPPD-NTBC ~~complex~~	+	Description: Crystal structure of human HPPD complexed with NTBC
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Yang, G.-F]]		[[Category: Yang, G.-F]]
	[[Category: Lin, H.-Y]]		[[Category: Lin, H.-Y]]
	[[Category: Dong, J]]		[[Category: Dong, J]]

OCA at 14:55, 26 April 2023

OCA — Wed, 26 Apr 2023 14:55:13 GMT

←Older revision		Revision as of 14:55, 26 April 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8im2 is ON HOLD	+	The entry 8im2 is ON HOLD until Paper Publication

	Authors: Dong, J., Yang, G.-F., Lin, H.-Y.		Authors: Dong, J., Yang, G.-F., Lin, H.-Y.

OCA: Protected "8im2" [edit=sysop:move=sysop]

OCA — Wed, 15 Mar 2023 08:12:10 GMT

Protected "8im2" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:12, 15 March 2023

OCA: New page: '''Unreleased structure''' The entry 8im2 is ON HOLD Authors: Dong, J., Yang, G.-F., Lin, H.-Y. Description: Crystal structure of human HPPD-NTBC complex [[Category: Unreleased Structu...

OCA — Wed, 15 Mar 2023 08:12:06 GMT

New page: '''Unreleased structure''' The entry 8im2 is ON HOLD Authors: Dong, J., Yang, G.-F., Lin, H.-Y. Description: Crystal structure of human HPPD-NTBC complex [[Category: Unreleased Structu...

New page

'''Unreleased structure'''

The entry 8im2 is ON HOLD

Authors: Dong, J., Yang, G.-F., Lin, H.-Y.

Description: Crystal structure of human HPPD-NTBC complex
[[Category: Unreleased Structures]]
[[Category: Yang, G.-F]]
[[Category: Lin, H.-Y]]
[[Category: Dong, J]]