7n66 - Revision history

OCA at 16:24, 18 October 2023

OCA — Wed, 18 Oct 2023 16:24:50 GMT

←Older revision		Revision as of 16:24, 18 October 2023
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	<StructureSection load='7n66' size='340' side='right'caption='[[7n66]], [[Resolution\|resolution]] 2.10Å' scene=''>		<StructureSection load='7n66' size='340' side='right'caption='[[7n66]], [[Resolution\|resolution]] 2.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7n66]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N66 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7n66]] 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=7N66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N66 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EW:N-{3-[(2S,5R)-6-amino-5-(ethanesulfonyl)-2-(fluoromethyl)-5-methyl-2,3,4,5-tetrahydropyridin-2-yl]-4-fluorophenyl}-2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine-6-carboxamide'>0EW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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]] 2.1Å</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0EW:N-{3-[(2S,5R)-6-amino-5-(ethanesulfonyl)-2-(fluoromethyl)-5-methyl-2,3,4,5-tetrahydropyridin-2-yl]-4-fluorophenyl}-2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine-6-carboxamide'>0EW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=7n66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n66 OCA], [https://pdbe.org/7n66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n66 RCSB], [https://www.ebi.ac.uk/pdbsum/7n66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n66 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=7n66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n66 OCA], [https://pdbe.org/7n66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n66 RCSB], [https://www.ebi.ac.uk/pdbsum/7n66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n66 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[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>	+	[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 ==
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	</div>		</div>
	<div class="pdbe-citations 7n66" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7n66" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Beta secretase 3D structures\|Beta secretase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Memapsin 2]]~~	+	[[Category: Shaffer PL]]
-	[[Category: Shaffer~~, P L]]~~	+
-	~~[[Category: Bace protease]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase-inhibitor complex~~]]	+

OCA at 15:52, 27 October 2021

OCA — Wed, 27 Oct 2021 15:52:45 GMT

←Older revision		Revision as of 15:52, 27 October 2021
Line 1:		Line 1:

	==BACE-1 in complex with ligand 12==		==BACE-1 in complex with ligand 12==
-	<StructureSection load='7n66' size='340' side='right'caption='[[7n66]]' scene=''>	+	<StructureSection load='7n66' size='340' side='right'caption='[[7n66]], [[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=7N66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N66 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7n66]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N66 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=7n66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n66 OCA], [https://pdbe.org/7n66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n66 RCSB], [https://www.ebi.ac.uk/pdbsum/7n66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n66 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=0EW:N-{3-[(2S,5R)-6-amino-5-(ethanesulfonyl)-2-(fluoromethyl)-5-methyl-2,3,4,5-tetrahydropyridin-2-yl]-4-fluorophenyl}-2,2-difluoro-2H-[1,3]dioxolo[4,5-c]pyridine-6-carboxamide'>0EW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7n66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n66 OCA], [https://pdbe.org/7n66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n66 RCSB], [https://www.ebi.ac.uk/pdbsum/7n66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n66 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[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;">
		+	== Publication Abstract from PubMed ==
		+	The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid beta lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.
		+
		+	JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.,Rombouts FJR, Kusakabe KI, Alexander R, Austin N, Borghys H, De Cleyn M, Dhuyvetter D, Gijsen HJM, Hrupka B, Jacobs T, Jerhaoui S, Lammens L, Leclercq L, Tsubone K, Ueno T, Morimoto K, Einaru S, Sumiyoshi H, Van den Bergh A, Vos A, Surkyn M, Teisman A, Moechars D J Med Chem. 2021 Sep 23. doi: 10.1021/acs.jmedchem.1c00935. PMID:34553934<ref>PMID:34553934</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7n66" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Shaffer PL]]	+	[[Category: Memapsin 2]]
		+	[[Category: Shaffer, P L]]
		+	[[Category: Bace protease]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase-inhibitor complex]]

OCA at 05:31, 6 October 2021

OCA — Wed, 06 Oct 2021 05:31:54 GMT

←Older revision		Revision as of 05:31, 6 October 2021
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-	'''Unreleased structure'''

-	~~The entry~~ 7n66 ~~is ON HOLD until Paper Publication~~	+	==BACE-1 in complex with ligand 12==
-		+	<StructureSection load='7n66' size='340' side='right'caption='[[7n66]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N66 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N66 FirstGlance]. <br>
-	~~Description~~:	+	</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=7n66 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n66 OCA], [https://pdbe.org/7n66 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n66 RCSB], [https://www.ebi.ac.uk/pdbsum/7n66 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n66 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Shaffer PL]]

OCA at 02:29, 2 July 2021

OCA — Fri, 02 Jul 2021 02:29:06 GMT

←Older revision		Revision as of 02:29, 2 July 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7n66 is ON HOLD	+	The entry 7n66 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7n66" [edit=sysop:move=sysop]

OCA — Thu, 17 Jun 2021 13:40:52 GMT

Protected "7n66" [edit=sysop:move=sysop]

←Older revision

Revision as of 13:40, 17 June 2021

OCA: New page: '''Unreleased structure''' The entry 7n66 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Thu, 17 Jun 2021 13:40:51 GMT

New page: '''Unreleased structure''' The entry 7n66 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7n66 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]