4rce - Revision history

OCA at 06:49, 2 March 2023

OCA — Thu, 02 Mar 2023 06:49:44 GMT

←Older revision		Revision as of 06:49, 2 March 2023
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	<StructureSection load='4rce' size='340' side='right'caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='4rce' size='340' side='right'caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rce]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RCE OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4RCE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rce]] is a 1 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=4RCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RCE FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</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=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [https://pdbe.org/4rce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [https://www.ebi.ac.uk/pdbsum/4rce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://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'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>	+
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [~~http~~://pdbe.org/4rce PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4rce PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>	+	[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Memapsin 2]]~~	+	[[Category: Long AM]]
-	[[Category: Long~~, A M~~]]	+	[[Category: Whittington DA]]
-	[[Category: Whittington~~, D A]]~~	+
-	~~[[Category: Alzheimer's disease]]~~	+
-	~~[[Category: Amyloid precursor protein]]~~	+
-	~~[[Category: App]]~~	+
-	~~[[Category: Aspartic protease]]~~	+
-	~~[[Category: Brain]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex~~]]	+

OCA at 10:40, 1 May 2019

OCA — Wed, 01 May 2019 10:40:43 GMT

←Older revision		Revision as of 10:40, 1 May 2019
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	==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==		==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==
-	<StructureSection load='4rce' size='340' side='right' caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>	+	<StructureSection load='4rce' size='340' side='right'caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4rce]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RCE FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4rce]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RCE FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, KIAA1149 ([http://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'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [http://pdbe.org/4rce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [http://www.ebi.ac.uk/pdbsum/4rce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [http://pdbe.org/4rce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [http://www.ebi.ac.uk/pdbsum/4rce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce ProSAT]</span></td></tr>
Line 22:		Line 23:

	==See Also==		==See Also==
-	*[[Beta secretase\|Beta secretase]]	+	*[[Beta secretase 3D structures\|Beta secretase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Memapsin 2]]		[[Category: Memapsin 2]]
	[[Category: Long, A M]]		[[Category: Long, A M]]

OCA at 08:05, 11 August 2016

OCA — Thu, 11 Aug 2016 08:05:23 GMT

←Older revision		Revision as of 08:05, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==		==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==
	<StructureSection load='4rce' size='340' side='right' caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>		<StructureSection load='4rce' size='340' side='right' caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [http://www.ebi.ac.uk/pdbsum/4rce PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [http://pdbe.org/4rce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [http://www.ebi.ac.uk/pdbsum/4rce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4rce ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4rce" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Beta secretase\|Beta secretase]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 07:38, 24 December 2014

OCA — Wed, 24 Dec 2014 07:38:55 GMT

←Older revision		Revision as of 07:38, 24 December 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2==
		+	<StructureSection load='4rce' size='340' side='right' caption='[[4rce]], [[Resolution\|resolution]] 2.40Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4rce]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RCE FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LN:(4S)-2-(2,2-DIMETHYLPROPOXY)-7-(PYRIMIDIN-5-YL)SPIRO[1,3-OXAZOLE-4,9-XANTHEN]-2-AMINE'>3LN</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4rcd\|4rcd]], [[4rcf\|4rcf]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4rce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rce OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rce RCSB], [http://www.ebi.ac.uk/pdbsum/4rce PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN]] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The optimization of a series of aminooxazoline xanthene inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Abeta lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Abeta reduction in a rat pharmacodynamic model (78% Abeta reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

-	~~The entry 4rce is ON HOLD until Paper Publication~~	+	Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.,Epstein O, Bryan MC, Cheng AC, Derakhchan K, Dineen TA, Hickman D, Hua Z, Human JB, Kreiman C, Marx IE, Weiss MM, Wahl RC, Wen PH, Whittington DA, Wood S, Zheng XM, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9796-810. doi: 10.1021/jm501266w. Epub 2014 Nov, 12. PMID:25389560<ref>PMID:25389560</ref>

-	~~Authors: Whittington~~, D.A., Long, A.M.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal structure of BACE1 in complex with aminooxazoline xanthene~~ inhibitor 2	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Memapsin 2]]
		+	[[Category: Long, A M]]
		+	[[Category: Whittington, D A]]
		+	[[Category: Alzheimer's disease]]
		+	[[Category: Amyloid precursor protein]]
		+	[[Category: App]]
		+	[[Category: Aspartic protease]]
		+	[[Category: Brain]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]

OCA at 06:30, 8 October 2014

OCA — Wed, 08 Oct 2014 06:30:51 GMT

←Older revision		Revision as of 06:30, 8 October 2014
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4rce is ON HOLD	+	The entry 4rce is ON HOLD until Paper Publication

	Authors: Whittington, D.A., Long, A.M.		Authors: Whittington, D.A., Long, A.M.

	Description: Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2		Description: Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2

OCA: Protected "4rce" [edit=sysop:move=sysop]

OCA — Wed, 24 Sep 2014 08:32:48 GMT

Protected "4rce" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:32, 24 September 2014

OCA: New page: '''Unreleased structure''' The entry 4rce is ON HOLD Authors: Whittington, D.A., Long, A.M. Description: Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2

OCA — Wed, 24 Sep 2014 08:32:47 GMT

New page: '''Unreleased structure''' The entry 4rce is ON HOLD Authors: Whittington, D.A., Long, A.M. Description: Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2

New page

'''Unreleased structure'''

The entry 4rce is ON HOLD

Authors: Whittington, D.A., Long, A.M.

Description: Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2