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| | <StructureSection load='5enm' size='340' side='right'caption='[[5enm]], [[Resolution|resolution]] 1.98Å' scene=''> | | <StructureSection load='5enm' size='340' side='right'caption='[[5enm]], [[Resolution|resolution]] 1.98Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5enm]] 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=5ENM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ENM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5enm]] 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=5ENM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ENM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QU:(2~{R},4~{S},6~{S})-4-[2,4-BIS(FLUORANYL)-5-PYRIMIDIN-5-YL-PHENYL]-6-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-1,3-THIAZINAN-2-AMINE'>5QU</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]] 1.98Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5enk|5enk]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QU:(2~{R},4~{S},6~{S})-4-[2,4-BIS(FLUORANYL)-5-PYRIMIDIN-5-YL-PHENYL]-6-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-1,3-THIAZINAN-2-AMINE'>5QU</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5enm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enm OCA], [https://pdbe.org/5enm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5enm RCSB], [https://www.ebi.ac.uk/pdbsum/5enm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5enm ProSAT]</span></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'>[http://proteopedia.org/fgij/fg.htm?mol=5enm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enm OCA], [http://pdbe.org/5enm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5enm RCSB], [http://www.ebi.ac.uk/pdbsum/5enm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5enm 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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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Memapsin 2]]
| + | [[Category: Lewis HA]] |
| - | [[Category: Lewis, H A]] | + | |
| - | [[Category: Bace]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| 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 targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Abeta reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.
Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Abeta Reduction in Rodents.,Wu YJ, Guernon J, Yang F, Snyder L, Shi J, Mcclure A, Rajamani R, Park H, Ng A, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA ACS Med Chem Lett. 2016 Jan 11;7(3):271-6. doi: 10.1021/acsmedchemlett.5b00432., eCollection 2016 Mar 10. PMID:26985314[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
- ↑ Wu YJ, Guernon J, Yang F, Snyder L, Shi J, Mcclure A, Rajamani R, Park H, Ng A, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Abeta Reduction in Rodents. ACS Med Chem Lett. 2016 Jan 11;7(3):271-6. doi: 10.1021/acsmedchemlett.5b00432., eCollection 2016 Mar 10. PMID:26985314 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00432
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