6jt3

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'''Unreleased structure'''
 
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The entry 6jt3 is ON HOLD
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==Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide==
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<StructureSection load='6jt3' size='340' side='right'caption='[[6jt3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6jt3]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6JT3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6JT3 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C83:N-[3-[(4R,5R,6R)-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide'>C83</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>
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<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>
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<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=6jt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jt3 OCA], [http://pdbe.org/6jt3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6jt3 RCSB], [http://www.ebi.ac.uk/pdbsum/6jt3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6jt3 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Genetic evidence points to deposition of amyloid-beta (Abeta) as a causal factor for Alzheimer's disease. Abeta generation is initiated when beta-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Abeta reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Abeta reduction of 80% at trough level.
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Authors: Tadano, G., Komano, K., Yoshida, S., Suzuki, S., Nakahara, K., Fuchino, K., Fujimoto, K., Matsuoka, E., Yamamoto, T., Asada, N., Ito, H., Sakaguchi, G., Kanegawa, N., Kido, Y., Ando, S., Fukushima, T., Teisman, A., Urmaliya, V., Dhuyvetter, D., Borghys, H., Bergh, A.V.D., Austin, N., Gijsen, H.J.M., Yamano, Y., Iso, Y., Kusakabe, K.I.
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Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.,Tadano G, Komano K, Yoshida S, Suzuki S, Nakahara K, Fuchino K, Fujimoto K, Matsuoka E, Yamamoto T, Asada N, Ito H, Sakaguchi G, Kanegawa N, Kido Y, Ando S, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Van Den Bergh A, Austin N, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140. Epub, 2019 Oct 8. PMID:31549838<ref>PMID:31549838</ref>
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Description: Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Teisman, A]]
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<div class="pdbe-citations 6jt3" style="background-color:#fffaf0;"></div>
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[[Category: Yamamoto, T]]
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== References ==
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[[Category: Fujimoto, K]]
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<references/>
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[[Category: Gijsen, H.J.M]]
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__TOC__
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[[Category: Matsuoka, E]]
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</StructureSection>
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[[Category: Yamano, Y]]
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[[Category: Large Structures]]
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[[Category: Sakaguchi, G]]
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[[Category: Memapsin 2]]
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[[Category: Suzuki, S]]
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[[Category: Komano, K]]
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[[Category: Iso, Y]]
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[[Category: Fukushima, T]]
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[[Category: Asada, N]]
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[[Category: Urmaliya, V]]
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[[Category: Yoshida, S]]
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[[Category: Dhuyvetter, D]]
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[[Category: Ando, S]]
[[Category: Ando, S]]
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[[Category: Nakahara, K]]
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[[Category: Asada, N]]
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[[Category: Kusakabe, K.I]]
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[[Category: Austin, N]]
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[[Category: Bergh, A.V.D]]
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[[Category: Bergh, A V.D]]
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[[Category: Tadano, G]]
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[[Category: Borghys, H]]
[[Category: Borghys, H]]
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[[Category: Dhuyvetter, D]]
[[Category: Fuchino, K]]
[[Category: Fuchino, K]]
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[[Category: Fujimoto, K]]
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[[Category: Fukushima, T]]
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[[Category: Gijsen, H J.M]]
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[[Category: Iso, Y]]
[[Category: Ito, H]]
[[Category: Ito, H]]
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[[Category: Austin, N]]
 
[[Category: Kanegawa, N]]
[[Category: Kanegawa, N]]
[[Category: Kido, Y]]
[[Category: Kido, Y]]
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[[Category: Komano, K]]
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[[Category: Kusakabe, K I]]
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[[Category: Matsuoka, E]]
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[[Category: Nakahara, K]]
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[[Category: Sakaguchi, G]]
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[[Category: Suzuki, S]]
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[[Category: Tadano, G]]
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[[Category: Teisman, A]]
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[[Category: Urmaliya, V]]
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[[Category: Yamamoto, T]]
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[[Category: Yamano, Y]]
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[[Category: Yoshida, S]]
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[[Category: Hydrolase]]

Revision as of 09:03, 30 October 2019

Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide

PDB ID 6jt3

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