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| - | [[Image:2qmf.jpg|left|200px]] | |
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| - | {{Structure
| + | ==Structure of BACE Bound to SCH735310== |
| - | |PDB= 2qmf |SIZE=350|CAPTION= <scene name='initialview01'>2qmf</scene>, resolution 1.750Å
| + | <StructureSection load='2qmf' size='340' side='right'caption='[[2qmf]], [[Resolution|resolution]] 1.75Å' scene=''> |
| - | |SITE= <scene name='pdbsite=AC1:Cs9+Binding+Site+For+Residue+A+1'>AC1</scene>, <scene name='pdbsite=AC2:Cs9+Binding+Site+For+Residue+B+1'>AC2</scene>, <scene name='pdbsite=AC3:Tar+Binding+Site+For+Residue+A+2'>AC3</scene> and <scene name='pdbsite=AC4:Tar+Binding+Site+For+Residue+B+3'>AC4</scene>
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=CS9:N'-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R,4R)-4-PHENOXYPYRROLIDIN-2-YL]ETHYL}-5-METHYL-N,N-DIPROPYLISOPHTHALAMIDE'>CS9</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene>
| + | <table><tr><td colspan='2'>[[2qmf]] 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=2QMF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QMF FirstGlance]. <br> |
| - | |ACTIVITY= <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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> |
| - | |GENE= BACE1, BACE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CS9:N-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-2-[(2R,4R)-4-PHENOXYPYRROLIDIN-2-YL]ETHYL}-5-METHYL-N,N-DIPROPYLISOPHTHALAMIDE'>CS9</scene>, <scene name='pdbligand=TAR:D(-)-TARTARIC+ACID'>TAR</scene></td></tr> |
| - | |DOMAIN=
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2qmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qmf OCA], [https://pdbe.org/2qmf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qmf RCSB], [https://www.ebi.ac.uk/pdbsum/2qmf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qmf ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=[[2qk5|2qk5]], [[2qkj|2qkj]], [[2qmd|2qmd]], [[2qmg|2qmg]], [[2qp8|2qp8]]
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qmf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qmf OCA], [http://www.ebi.ac.uk/pdbsum/2qmf PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qmf RCSB]</span>
| + | == Function == |
| - | }}
| + | [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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/qm/2qmf_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2qmf ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date. |
| | | | |
| - | '''Structure of BACE Bound to SCH735310'''
| + | Potent pyrrolidine- and piperidine-based BACE-1 inhibitors.,Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker EM, Strickland C, Voigt J Bioorg Med Chem Lett. 2008 Jan 1;18(1):414-7. Epub 2007 Nov 6. PMID:18023580<ref>PMID:18023580</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 2qmf" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Overview== | + | ==See Also== |
| - | Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date.
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure==
| + | <references/> |
| - | 2QMF is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QMF OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference== | + | |
| - | Potent pyrrolidine- and piperidine-based BACE-1 inhibitors., Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker EM, Strickland C, Voigt J, Bioorg Med Chem Lett. 2008 Jan 1;18(1):414-7. Epub 2007 Nov 6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18023580 18023580]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Single protein]]
| + | [[Category: Iserloh U]] |
| - | [[Category: Iserloh, U.]] | + | [[Category: Strickland CO]] |
| - | [[Category: Strickland, C O.]] | + | |
| - | [[Category: alternative splicing]]
| + | |
| - | [[Category: aspartyl protease]]
| + | |
| - | [[Category: bace1]]
| + | |
| - | [[Category: glycoprotein]]
| + | |
| - | [[Category: hydrolase]]
| + | |
| - | [[Category: membrane]]
| + | |
| - | [[Category: protease]]
| + | |
| - | [[Category: transmembrane]]
| + | |
| - | [[Category: zymogen]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:50:52 2008''
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Based on lead compound 1 identified from the patent literature, we developed novel patentable BACE-1 inhibitors by introducing a cyclic amine scaffold. Extensive SAR studies on both pyrrolidines and piperidines ultimately led to inhibitor 2f, one of the most potent inhibitors synthesized to date.
Potent pyrrolidine- and piperidine-based BACE-1 inhibitors.,Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker EM, Strickland C, Voigt J Bioorg Med Chem Lett. 2008 Jan 1;18(1):414-7. Epub 2007 Nov 6. PMID:18023580[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
- ↑ Iserloh U, Wu Y, Cumming JN, Pan J, Wang LY, Stamford AW, Kennedy ME, Kuvelkar R, Chen X, Parker EM, Strickland C, Voigt J. Potent pyrrolidine- and piperidine-based BACE-1 inhibitors. Bioorg Med Chem Lett. 2008 Jan 1;18(1):414-7. Epub 2007 Nov 6. PMID:18023580 doi:10.1016/j.bmcl.2007.10.116
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