6jsz
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 6jsz is ON HOLD Authors: Fujimoto, K., Matsuoka, E., Asada, N., Tadano, G., Yamamoto, T., Nakahara, K., Fuchino, K., Ito, H., Kanegawa, N., Moechars...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==BACE2 xaperone complex with N-{3-[(5R)-3-amino-5-methyl-9,9-dioxo-2,9lambda6-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide== | |
| + | <StructureSection load='6jsz' size='340' side='right'caption='[[6jsz]], [[Resolution|resolution]] 1.53Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6jsz]] 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=6JSZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JSZ FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.53Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C7O:~{N}-[3-[(5~{R})-3-azanyl-5-methyl-9,9-bis(oxidanylidene)-2,9$l^{6}-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide'>C7O</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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=6jsz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jsz OCA], [https://pdbe.org/6jsz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jsz RCSB], [https://www.ebi.ac.uk/pdbsum/6jsz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jsz ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BACE2_HUMAN BACE2_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading 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. It has also been shown that it can cleave APP between residues 671 and 672.<ref>PMID:10591213</ref> <ref>PMID:11083922</ref> <ref>PMID:15857888</ref> <ref>PMID:11423558</ref> <ref>PMID:16816112</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | BACE1 inhibitors hold potential as agents in disease-modifying treatment for Alzheimer's disease. BACE2 cleaves the melanocyte protein PMEL in pigment cells of the skin and eye, generating melanin pigments. This role of BACE2 implies that nonselective and chronic inhibition of BACE1 may cause side effects derived from BACE2. Herein, we describe the discovery of potent and selective BACE1 inhibitors using structure-based drug design. We targeted the flap region, where the shape and flexibility differ between these enzymes. Analysis of the cocrystal structures of an initial lead 8 prompted us to incorporate spirocycles followed by its fine-tuning, culminating in highly selective compounds 21 and 22. The structures of 22 bound to BACE1 and BACE2 revealed that a relatively high energetic penalty in the flap of the 22-bound BACE2 structure may cause a loss in BACE2 potency, thereby leading to its high selectivity. These findings and insights should contribute to responding to the challenges in exploring selective BACE1 inhibitors. | ||
| - | + | Structure-Based Design of Selective beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: Targeting the Flap to Gain Selectivity over BACE2.,Fujimoto K, Matsuoka E, Asada N, Tadano G, Yamamoto T, Nakahara K, Fuchino K, Ito H, Kanegawa N, Moechars D, Gijsen HJM, Kusakabe KI J Med Chem. 2019 May 23;62(10):5080-5095. doi: 10.1021/acs.jmedchem.9b00309. Epub, 2019 May 13. PMID:31021626<ref>PMID:31021626</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6jsz" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: | + | ==See Also== |
| - | [[Category: | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Asada N]] |
| - | [[Category: | + | [[Category: Fuchino K]] |
| + | [[Category: Fujimoto K]] | ||
| + | [[Category: Gijsen HJM]] | ||
| + | [[Category: Ito H]] | ||
| + | [[Category: Kanegawa N]] | ||
| + | [[Category: Kusakabe KI]] | ||
| + | [[Category: Matsuoka E]] | ||
| + | [[Category: Moechars D]] | ||
| + | [[Category: Nakahara K]] | ||
| + | [[Category: Tadano G]] | ||
| + | [[Category: Yamamoto T]] | ||
Current revision
BACE2 xaperone complex with N-{3-[(5R)-3-amino-5-methyl-9,9-dioxo-2,9lambda6-dithia-4-azaspiro[5.5]undec-3-en-5-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide
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Categories: Homo sapiens | Large Structures | Asada N | Fuchino K | Fujimoto K | Gijsen HJM | Ito H | Kanegawa N | Kusakabe KI | Matsuoka E | Moechars D | Nakahara K | Tadano G | Yamamoto T
