6q3x - Revision history

OCA at 11:52, 24 January 2024

OCA — Wed, 24 Jan 2024 11:52:19 GMT

←Older revision		Revision as of 11:52, 24 January 2024
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	==Structure of human galactokinase in complex with galactose and 2'-(benzo[d]oxazol-2-ylamino)-7',8'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'(6'H)-one==		==Structure of human galactokinase in complex with galactose and 2'-(benzo[d]oxazol-2-ylamino)-7',8'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'(6'H)-one==
-	<StructureSection load='6q3x' size='340' side='right'caption='[[6q3x]]' scene=''>	+	<StructureSection load='6q3x' size='340' side='right'caption='[[6q3x]], [[Resolution\|resolution]] 2.10Å' 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=6Q3X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q3X FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6q3x]] 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=6Q3X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q3X 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=6q3x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3x OCA], [https://pdbe.org/6q3x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q3x RCSB], [https://www.ebi.ac.uk/pdbsum/6q3x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3x 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]] 2.1Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GAL:BETA-D-GALACTOSE'>GAL</scene>, <scene name='pdbligand=HFK:2-(1,3-benzoxazol-2-ylamino)spiro[1,6,7,8-tetrahydroquinazoline-4,1-cyclohexane]-5-one'>HFK</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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=6q3x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3x OCA], [https://pdbe.org/6q3x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q3x RCSB], [https://www.ebi.ac.uk/pdbsum/6q3x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3x ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN] Defects in GALK1 are the cause of galactosemia II (GALCT2) [MIM:[https://omim.org/entry/230200 230200]. Galactosemia II is an autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses.<ref>PMID:10521295</ref> <ref>PMID:10790206</ref> <ref>PMID:11231902</ref> <ref>PMID:11139256</ref> <ref>PMID:12694189</ref> <ref>PMID:15024738</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN] Major enzyme for galactose metabolism.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Classic galactosemia is caused by loss-of-function mutations in galactose-1-phosphate uridylyltransferase (GALT) that lead to toxic accumulation of its substrate, galactose-1-phosphate. One proposed therapy is to inhibit the biosynthesis of galactose-1-phosphate, catalyzed by galactokinase 1 (GALK1). Existing inhibitors of human GALK1 (hGALK1) are primarily ATP-competitive with limited clinical utility to date. Here, we determined crystal structures of hGALK1 bound with reported ATP-competitive inhibitors of the spiro-benzoxazole series, to reveal their binding mode in the active site. Spurred by the need for additional chemotypes of hGALK1 inhibitors, desirably targeting a nonorthosteric site, we also performed crystallography-based screening by soaking hundreds of hGALK1 crystals, already containing active site ligands, with fragments from a custom library. Two fragments were found to bind close to the ATP binding site, and a further eight were found in a hotspot distal from the active site, highlighting the strength of this method in identifying previously uncharacterized allosteric sites. To generate inhibitors of improved potency and selectivity targeting the newly identified binding hotspot, new compounds were designed by merging overlapping fragments. This yielded two micromolar inhibitors of hGALK1 that were not competitive with respect to either substrate (ATP or galactose) and demonstrated good selectivity over hGALK1 homologues, galactokinase 2 and mevalonate kinase. Our findings are therefore the first to demonstrate inhibition of hGALK1 from an allosteric site, with potential for further development of potent and selective inhibitors to provide novel therapeutics for classic galactosemia.
		+
		+	Fragment Screening Reveals Starting Points for Rational Design of Galactokinase 1 Inhibitors to Treat Classic Galactosemia.,Mackinnon SR, Krojer T, Foster WR, Diaz-Saez L, Tang M, Huber KVM, von Delft F, Lai K, Brennan PE, Arruda Bezerra G, Yue WW ACS Chem Biol. 2021 Mar 16. doi: 10.1021/acschembio.0c00498. PMID:33724769<ref>PMID:33724769</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6q3x" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
	*[[Galactokinase\|Galactokinase]]		*[[Galactokinase\|Galactokinase]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Arrowsmith C]]		[[Category: Arrowsmith C]]

OCA at 10:39, 28 July 2021

OCA — Wed, 28 Jul 2021 10:39:52 GMT

←Older revision		Revision as of 10:39, 28 July 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 6q3x is ~~ON HOLD until Paper Publication~~	+	==Structure of human galactokinase in complex with galactose and 2'-(benzo[d]oxazol-2-ylamino)-7',8'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'(6'H)-one==
		+	<StructureSection load='6q3x' size='340' side='right'caption='[[6q3x]]' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q3X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Q3X 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=6q3x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q3x OCA], [https://pdbe.org/6q3x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6q3x RCSB], [https://www.ebi.ac.uk/pdbsum/6q3x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6q3x ProSAT]</span></td></tr>
		+	</table>

-	~~Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W.W., Structural Genomics Consortium (SGC)~~	+	==See Also==
-		+	*[[Galactokinase\|Galactokinase]]
-	~~Description: Structure of human galactokinase in complex with galactose and 2'-(benzo~~[~~d]oxazol-2-ylamino)-7',8'-dihydro-1'H-spiro~~[~~cyclohexane-1,4'-quinazolin~~]~~-5'(6'H)-one~~	+	__TOC__
-	[[Category: ~~Unreleased~~ Structures]]	+	</StructureSection>
-	[[Category: ~~Foster, W~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Zhang, M~~]]	+	[[Category: Arrowsmith C]]
-	[[Category: ~~Mackinnon, S~~]]	+	[[Category: Bailey H]]
-	[[Category: ~~Lai, K~~]]	+	[[Category: Bezerra GA]]
-	[[Category: ~~Bezerra, G.~~A]]	+	[[Category: Bountra C]]
-	[[Category: ~~Structural Genomics Consortium (Sgc)~~]]	+	[[Category: Edwards A]]
-	[[Category: ~~Edwards, A~~]]	+	[[Category: Foster W]]
-	[[Category: ~~Yue, W.W~~]]	+	[[Category: Lai K]]
-	[[Category: ~~Bailey, H~~]]	+	[[Category: Mackinnon S]]
-	[[Category: ~~Bountra, C]]~~	+	[[Category: Yue WW]]
-	~~[[Category: Arrowsmith, C~~]]	+	[[Category: Zhang M]]

OCA at 06:53, 26 December 2018

OCA — Wed, 26 Dec 2018 06:53:24 GMT

←Older revision		Revision as of 06:53, 26 December 2018
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6q3x is ON HOLD	+	The entry 6q3x is ON HOLD until Paper Publication

	Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W.W., Structural Genomics Consortium (SGC)		Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W.W., Structural Genomics Consortium (SGC)

OCA: Protected "6q3x" [edit=sysop:move=sysop]

OCA — Wed, 12 Dec 2018 05:32:34 GMT

Protected "6q3x" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:32, 12 December 2018

OCA: New page: '''Unreleased structure''' The entry 6q3x is ON HOLD Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W....

OCA — Wed, 12 Dec 2018 05:32:33 GMT

New page: '''Unreleased structure''' The entry 6q3x is ON HOLD Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W....

New page

'''Unreleased structure'''

The entry 6q3x is ON HOLD

Authors: Bezerra, G.A., Mackinnon, S., Zhang, M., Foster, W., Bailey, H., Arrowsmith, C., Edwards, A., Bountra, C., Lai, K., Yue, W.W., Structural Genomics Consortium (SGC)

Description: Structure of human galactokinase in complex with galactose and 2'-(benzo[d]oxazol-2-ylamino)-7',8'-dihydro-1'H-spiro[cyclohexane-1,4'-quinazolin]-5'(6'H)-one
[[Category: Unreleased Structures]]
[[Category: Foster, W]]
[[Category: Zhang, M]]
[[Category: Mackinnon, S]]
[[Category: Lai, K]]
[[Category: Bezerra, G.A]]
[[Category: Structural Genomics Consortium (Sgc)]]
[[Category: Edwards, A]]
[[Category: Yue, W.W]]
[[Category: Bailey, H]]
[[Category: Bountra, C]]
[[Category: Arrowsmith, C]]