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| | <StructureSection load='4b77' size='340' side='right'caption='[[4b77]], [[Resolution|resolution]] 1.80Å' scene=''> | | <StructureSection load='4b77' size='340' side='right'caption='[[4b77]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4b77]] 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=4B77 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B77 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4b77]] 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=4B77 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B77 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=54M:(5R)-5-(4-METHOXYPHENYL)-5-(3-PYRIMIDIN-5-YLPHENYL)-3,4-DIHYDROPYRROL-2-AMINE'>54M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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]] 1.8Å</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]], [[4b00|4b00]], [[4b05|4b05]], [[4b0q|4b0q]], [[4b1c|4b1c]], [[4b1d|4b1d]], [[4b1e|4b1e]], [[4b70|4b70]], [[4b72|4b72]], [[4b78|4b78]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=54M:(5R)-5-(4-METHOXYPHENYL)-5-(3-PYRIMIDIN-5-YLPHENYL)-3,4-DIHYDROPYRROL-2-AMINE'>54M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=4b77 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b77 OCA], [https://pdbe.org/4b77 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b77 RCSB], [https://www.ebi.ac.uk/pdbsum/4b77 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b77 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=4b77 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b77 OCA], [http://pdbe.org/4b77 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b77 RCSB], [http://www.ebi.ac.uk/pdbsum/4b77 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b77 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 == |
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| | | | |
| | ==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: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Berg S]] |
| - | [[Category: Berg, S]] | + | [[Category: Blid J]] |
| - | [[Category: Blid, J]] | + | [[Category: Eketjall S]] |
| - | [[Category: Eketjall, S]] | + | [[Category: Falting J]] |
| - | [[Category: Falting, J]] | + | [[Category: Ginman T]] |
| - | [[Category: Ginman, T]] | + | [[Category: Gravenfors Y]] |
| - | [[Category: Gravenfors, Y]] | + | [[Category: Janson J]] |
| - | [[Category: Janson, J]] | + | [[Category: Jeppsson F]] |
| - | [[Category: Jeppsson, F]] | + | [[Category: Johansson P]] |
| - | [[Category: Johansson, P]] | + | [[Category: Karlstrom S]] |
| - | [[Category: Karlstrom, S]] | + | [[Category: Kieseritzky F]] |
| - | [[Category: Kieseritzky, F]] | + | [[Category: Kihlstrom J]] |
| - | [[Category: Kihlstrom, J]] | + | [[Category: Kolmodin K]] |
| - | [[Category: Kolmodin, K]] | + | [[Category: Lindstrom J]] |
| - | [[Category: Lindstrom, J]] | + | [[Category: Olsson L]] |
| - | [[Category: Olsson, L]] | + | [[Category: Rahm F]] |
| - | [[Category: Rahm, F]] | + | [[Category: Slivo C]] |
| - | [[Category: Slivo, C]] | + | [[Category: Stromberg K]] |
| - | [[Category: Stromberg, K]] | + | [[Category: Swahn B]] |
| - | [[Category: Swahn, B]] | + | [[Category: Viklund J]] |
| - | [[Category: Viklund, J]] | + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Lead generation]]
| + | |
| - | [[Category: Structure-based drug design]]
| + | |
| 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
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
Core Refinement toward Permeable beta-Secretase (BACE-1) Inhibitors with Low hERG Activity.,Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Forsblom R, Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting J, Gravenfors Y, Rahm F J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May, 20. PMID:23126626[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
- ↑ Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Forsblom R, Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting J, Gravenfors Y, Rahm F. Core Refinement toward Permeable beta-Secretase (BACE-1) Inhibitors with Low hERG Activity. J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May, 20. PMID:23126626 doi:10.1021/jm3011349
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