6zgy - Revision history

OCA at 13:49, 24 January 2024

2024-01-24T13:49:23Z

←Older revision		Revision as of 13:49, 24 January 2024
Line 3:		Line 3:
	<StructureSection load='6zgy' size='340' side='right'caption='[[6zgy]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='6zgy' size='340' side='right'caption='[[6zgy]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6zgy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6zgy]] is a 4 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=6ZGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGY FirstGlance]. <br>
-	</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=QL5:(2,5-dimethylphenyl)+pyridine-4-carboxylate'>QL5</scene~~></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]] 2.3Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GALK1, GALK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=QL5:(2,5-dimethylphenyl)+pyridine-4-carboxylate'>QL5</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] </span></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=6zgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgy OCA], [https://pdbe.org/6zgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgy RCSB], [https://www.ebi.ac.uk/pdbsum/6zgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgy ProSAT]</span></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=6zgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgy OCA], [https://pdbe.org/6zgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgy RCSB], [https://www.ebi.ac.uk/pdbsum/6zgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgy ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== 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>	+	[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 ==		== Function ==
-	[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Major enzyme for galactose metabolism.	+	[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN] Major enzyme for galactose metabolism.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 29:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Galactokinase]]~~	+	[[Category: Homo sapiens]]
-	~~[[Category: Human~~]]	+
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Arrowsmith, C]]	+	[[Category: Arrowsmith C]]
-	[[Category: Bezerra~~, G A~~]]	+	[[Category: Bezerra GA]]
-	[[Category: Bountra, C]]	+	[[Category: Bountra C]]
-	[[Category: Brandao-Neto, J]]	+	[[Category: Brandao-Neto J]]
-	[[Category: Brennan, P]]	+	[[Category: Brennan P]]
-	[[Category: Douangamath, A]]	+	[[Category: Douangamath A]]
-	[[Category: Edwards, A]]	+	[[Category: Edwards A]]
-	[[Category: Foster, W]]	+	[[Category: Foster W]]
-	[[Category: Krojer, T]]	+	[[Category: Krojer T]]
-	[[Category: Lai, K]]	+	[[Category: Lai K]]
-	[[Category: Mackinnon~~, S R~~]]	+	[[Category: Mackinnon SR]]
-	[[Category: Yue~~, W W~~]]	+	[[Category: Yue WW]]
-	[[Category: Zhang, M]]	+	[[Category: Zhang M]]
-	~~[[Category: Allosteric fragment]]~~	+
-	~~[[Category: Binding hotspt]]~~	+
-	~~[[Category: Fragment screening]]~~	+
-	~~[[Category: Galactokinase 1]]~~	+
-	~~[[Category: Galk1]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:06, 7 April 2021

2021-04-07T07:06:11Z

←Older revision		Revision as of 07:06, 7 April 2021
Line 1:		Line 1:

	==Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide==		==Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide==
-	<StructureSection load='6zgy' size='340' side='right'caption='[[6zgy]]' scene=''>	+	<StructureSection load='6zgy' size='340' side='right'caption='[[6zgy]], [[Resolution\|resolution]] 2.30Å' 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=6ZGY OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6ZGY FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6zgy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGY FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=6zgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgy OCA], [~~http~~://pdbe.org/6zgy PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6zgy RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6zgy PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgy ProSAT]</span></td></tr>	+	</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=QL5:(2,5-dimethylphenyl)+pyridine-4-carboxylate'>QL5</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GALK1, GALK ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] </span></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=6zgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgy OCA], [https://pdbe.org/6zgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgy RCSB], [https://www.ebi.ac.uk/pdbsum/6zgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgy 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 6zgy" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Galactokinase\|Galactokinase]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Galactokinase]]
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Arrowsmith C]]	+	[[Category: Arrowsmith, C]]
-	[[Category: Bezerra GA]]	+	[[Category: Bezerra, G A]]
-	[[Category: Bountra C]]	+	[[Category: Bountra, C]]
-	[[Category: Brandao-Neto J]]	+	[[Category: Brandao-Neto, J]]
-	[[Category: Brennan P]]	+	[[Category: Brennan, P]]
-	[[Category: Douangamath A]]	+	[[Category: Douangamath, A]]
-	[[Category: Edwards A]]	+	[[Category: Edwards, A]]
-	[[Category: Foster W]]	+	[[Category: Foster, W]]
-	[[Category: Krojer T]]	+	[[Category: Krojer, T]]
-	[[Category: Lai K]]	+	[[Category: Lai, K]]
-	[[Category: Mackinnon SR]]	+	[[Category: Mackinnon, S R]]
-	[[Category: Yue WW]]	+	[[Category: Yue, W W]]
-	[[Category: Zhang M]]	+	[[Category: Zhang, M]]
		+	[[Category: Allosteric fragment]]
		+	[[Category: Binding hotspt]]
		+	[[Category: Fragment screening]]
		+	[[Category: Galactokinase 1]]
		+	[[Category: Galk1]]
		+	[[Category: Transferase]]

OCA at 11:12, 29 July 2020

2020-07-29T11:12:53Z

←Older revision		Revision as of 11:12, 29 July 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 6zgy is ON HOLD~~	+	==Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide==
-		+	<StructureSection load='6zgy' size='340' side='right'caption='[[6zgy]]' scene=''>
-	~~Authors: Mackinnon, S.R., Bezerra, G.A., Zhang, M., Foster, W., Krojer, T., Brandao-Neto, J., Douangamath, A., Arrowsmith, C., Edwards, A., Bountra, C., Brennan, P., Lai, K., Yue, W.W.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGY OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZGY FirstGlance]. <br>
-	~~Description:~~ Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgy OCA], [http://pdbe.org/6zgy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zgy RCSB], [http://www.ebi.ac.uk/pdbsum/6zgy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgy ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Foster~~, W]]	+	__TOC__
-	[[Category: ~~Brandao-Neto, J~~]]	+	</StructureSection>
-	[[Category: ~~Lai, K~~]]	+	[[Category: Large Structures]]
-	[[Category: Bezerra~~, G.A~~]]	+	[[Category: Arrowsmith C]]
-	[[Category: ~~Yue, W.W~~]]	+	[[Category: Bezerra GA]]
-	[[Category: ~~Arrowsmith, C~~]]	+	[[Category: Bountra C]]
-	[[Category: ~~Zhang, M~~]]	+	[[Category: Brandao-Neto J]]
-	[[Category: ~~Edwards,~~ A]]	+	[[Category: Brennan P]]
-	[[Category: ~~Douangamath,~~ A]]	+	[[Category: Douangamath A]]
-	[[Category: ~~Mackinnon, S.R~~]]	+	[[Category: Edwards A]]
-	[[Category: Krojer, T]]	+	[[Category: Foster W]]
-	[[Category: ~~Brennan, P~~]]	+	[[Category: Krojer T]]
-	[[Category: ~~Bountra, C~~]]	+	[[Category: Lai K]]
		+	[[Category: Mackinnon SR]]
		+	[[Category: Yue WW]]
		+	[[Category: Zhang M]]

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

2020-07-08T11:07:02Z

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

←Older revision

Revision as of 11:07, 8 July 2020

OCA: New page: '''Unreleased structure''' The entry 6zgy is ON HOLD Authors: Mackinnon, S.R., Bezerra, G.A., Zhang, M., Foster, W., Krojer, T., Brandao-Neto, J., Douangamath, A., Arrowsmith, C., Edwar...

2020-07-08T11:07:01Z

New page: '''Unreleased structure''' The entry 6zgy is ON HOLD Authors: Mackinnon, S.R., Bezerra, G.A., Zhang, M., Foster, W., Krojer, T., Brandao-Neto, J., Douangamath, A., Arrowsmith, C., Edwar...

New page

'''Unreleased structure'''

The entry 6zgy is ON HOLD

Authors: Mackinnon, S.R., Bezerra, G.A., Zhang, M., Foster, W., Krojer, T., Brandao-Neto, J., Douangamath, A., Arrowsmith, C., Edwards, A., Bountra, C., Brennan, P., Lai, K., Yue, W.W.

Description: Structure of human galactokinase 1 bound with 2-(4-chlorophenyl)-N-(pyrimidin-2-yl)acetamide
[[Category: Unreleased Structures]]
[[Category: Foster, W]]
[[Category: Brandao-Neto, J]]
[[Category: Lai, K]]
[[Category: Bezerra, G.A]]
[[Category: Yue, W.W]]
[[Category: Arrowsmith, C]]
[[Category: Zhang, M]]
[[Category: Edwards, A]]
[[Category: Douangamath, A]]
[[Category: Mackinnon, S.R]]
[[Category: Krojer, T]]
[[Category: Brennan, P]]
[[Category: Bountra, C]]