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| | ==Bace1 in complex with the aminohydantoin Compound 102== | | ==Bace1 in complex with the aminohydantoin Compound 102== |
| - | <StructureSection load='3ooz' size='340' side='right' caption='[[3ooz]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='3ooz' size='340' side='right'caption='[[3ooz]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ooz]] 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=3OOZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OOZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ooz]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OOZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OOZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZOO:(5R)-2-AMINO-5-[4-(DIFLUOROMETHOXY)PHENYL]-5-[4-FLUORO-3-(5-FLUOROPENT-1-YN-1-YL)PHENYL]-3-METHYL-3,5-DIHYDRO-4H-IMIDAZOL-4-ONE'>ZOO</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZOO:(5R)-2-AMINO-5-[4-(DIFLUOROMETHOXY)PHENYL]-5-[4-FLUORO-3-(5-FLUOROPENT-1-YN-1-YL)PHENYL]-3-METHYL-3,5-DIHYDRO-4H-IMIDAZOL-4-ONE'>ZOO</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ooz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ooz OCA], [http://pdbe.org/3ooz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ooz RCSB], [http://www.ebi.ac.uk/pdbsum/3ooz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ooz ProSAT]</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=3ooz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ooz OCA], [https://pdbe.org/3ooz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ooz RCSB], [https://www.ebi.ac.uk/pdbsum/3ooz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ooz 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/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Memapsin 2]] | | [[Category: Memapsin 2]] |
| | [[Category: Olland, A M]] | | [[Category: Olland, A M]] |
| 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 identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Abeta40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..
Design and synthesis of aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors with enhanced brain permeability.,Malamas MS, Robichaud A, Erdei J, Quagliato D, Solvibile W, Zhou P, Morris K, Turner J, Wagner E, Fan K, Olland A, Jacobsen S, Reinhart P, Riddell D, Pangalos M Bioorg Med Chem Lett. 2010 Nov 15;20(22):6597-605. Epub 2010 Sep 15. PMID:20880704[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
- ↑ Malamas MS, Robichaud A, Erdei J, Quagliato D, Solvibile W, Zhou P, Morris K, Turner J, Wagner E, Fan K, Olland A, Jacobsen S, Reinhart P, Riddell D, Pangalos M. Design and synthesis of aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors with enhanced brain permeability. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6597-605. Epub 2010 Sep 15. PMID:20880704 doi:10.1016/j.bmcl.2010.09.029
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