|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='4b00' size='340' side='right'caption='[[4b00]], [[Resolution|resolution]] 1.83Å' scene=''> | | <StructureSection load='4b00' size='340' side='right'caption='[[4b00]], [[Resolution|resolution]] 1.83Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4b00]] 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=4B00 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B00 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4b00]] 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=4B00 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B00 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=I6X:5-{(1R)-3-AMINO-4-FLUORO-1-[3-(5-PROP-1-YN-1-YLPYRIDIN-3-YL)PHENYL]-1H-ISOINDOL-1-YL}-1-ETHYL-3-METHYLPYRIDIN-2(1H)-ONE'>I6X</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]] 1.83Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fkn|1fkn]], [[1m4h|1m4h]], [[1py1|1py1]], [[1sgz|1sgz]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1w50|1w50]], [[1w51|1w51]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1xs7|1xs7]], [[1ym2|1ym2]], [[1ym4|1ym4]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2fdp|2fdp]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]], [[2vij|2vij]], [[2viy|2viy]], [[2viz|2viz]], [[2vj6|2vj6]], [[2vj7|2vj7]], [[2vj9|2vj9]], [[2vkm|2vkm]], [[2vnm|2vnm]], [[2vnn|2vnn]], [[2wez|2wez]], [[2wf0|2wf0]], [[2wf1|2wf1]], [[2wf2|2wf2]], [[2wf3|2wf3]], [[2wf4|2wf4]], [[2wjo|2wjo]], [[2xfi|2xfi]], [[2xfj|2xfj]], [[2xfk|2xfk]], [[4acu|4acu]], [[4acx|4acx]], [[4azy|4azy]], [[4b05|4b05]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=I6X:5-{(1R)-3-AMINO-4-FLUORO-1-[3-(5-PROP-1-YN-1-YLPYRIDIN-3-YL)PHENYL]-1H-ISOINDOL-1-YL}-1-ETHYL-3-METHYLPYRIDIN-2(1H)-ONE'>I6X</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4b00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b00 OCA], [https://pdbe.org/4b00 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b00 RCSB], [https://www.ebi.ac.uk/pdbsum/4b00 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b00 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=4b00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b00 OCA], [http://pdbe.org/4b00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b00 RCSB], [http://www.ebi.ac.uk/pdbsum/4b00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b00 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 27: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Andersson L]] |
| - | [[Category: Andersson, L]] | + | [[Category: Berg S]] |
| - | [[Category: Berg, S]] | + | [[Category: Bergh M]] |
| - | [[Category: Berg, S von]]
| + | [[Category: Bogar K]] |
| - | [[Category: Bergh, M]] | + | [[Category: Eketjall S]] |
| - | [[Category: Bogar, K]] | + | [[Category: Falting J]] |
| - | [[Category: Eketjall, S]] | + | [[Category: Georgievska B]] |
| - | [[Category: Falting, J]] | + | [[Category: Holenz J]] |
| - | [[Category: Georgievska, B]] | + | [[Category: Janson J]] |
| - | [[Category: Holenz, J]] | + | [[Category: Jeppsson F]] |
| - | [[Category: Janson, J]] | + | [[Category: Karlstrom S]] |
| - | [[Category: Jeppsson, F]] | + | [[Category: Kers A]] |
| - | [[Category: Karlstrom, S]] | + | [[Category: Kihlstrom J]] |
| - | [[Category: Kers, A]] | + | [[Category: Kolmodin K]] |
| - | [[Category: Kihlstrom, J]] | + | [[Category: Lindstrom J]] |
| - | [[Category: Kolmodin, K]] | + | [[Category: Ohberg L]] |
| - | [[Category: Lindstrom, J]] | + | [[Category: Olsson LL]] |
| - | [[Category: Ohberg, L]] | + | [[Category: Pyring D]] |
| - | [[Category: Olsson, L L]] | + | [[Category: Slivo C]] |
| - | [[Category: Pyring, D]] | + | [[Category: Soderman P]] |
| - | [[Category: Slivo, C]] | + | [[Category: Sundstrom M]] |
| - | [[Category: Soderman, P]] | + | [[Category: Swahn BM]] |
| - | [[Category: Sundstrom, M]] | + | [[Category: Turek D]] |
| - | [[Category: Swahn, B M]] | + | [[Category: Von Berg S]] |
| - | [[Category: Turek, D]] | + | |
| - | [[Category: Alzheimer's disease]] | + | |
| - | [[Category: Aminoisoindole]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
The evaluation of a series of aminoisoindoles as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Abeta40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 muM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of beta-amyloid peptides in mouse brain following oral dosing.
Design and Synthesis of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of beta-Amyloid Peptides.,Swahn BM, Kolmodin K, Karlstrom S, von Berg S, Soderman P, Holenz J, Berg S, Lindstrom J, Sundstrom M, Turek D, Kihlstrom J, Slivo C, Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjall S, Georgievska B, Jeppsson F, Falting J J Med Chem. 2012 Sep 17. PMID:22924815[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ Swahn BM, Kolmodin K, Karlstrom S, von Berg S, Soderman P, Holenz J, Berg S, Lindstrom J, Sundstrom M, Turek D, Kihlstrom J, Slivo C, Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjall S, Georgievska B, Jeppsson F, Falting J. Design and Synthesis of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of beta-Amyloid Peptides. J Med Chem. 2012 Sep 17. PMID:22924815 doi:http://dx.doi.org/10.1021/jm3009025
|
