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[[Image:2qk5.jpg|left|200px]]


{{Structure
==Structure of BACE1 bound to SCH626485==
|PDB= 2qk5 |SIZE=350|CAPTION= <scene name='initialview01'>2qk5</scene>, resolution 2.200&Aring;
<StructureSection load='2qk5' size='340' side='right'caption='[[2qk5]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
|SITE= <scene name='pdbsite=AC1:Cs5+Binding+Site+For+Residue+A+1'>AC1</scene> and <scene name='pdbsite=AC2:Cs5+Binding+Site+For+Residue+B+1'>AC2</scene>
== Structural highlights ==
|LIGAND= <scene name='pdbligand=CS5:N&#39;-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-5-METHYL-N,N-DIPROPYLISOPHTHALAMIDE'>CS5</scene>
<table><tr><td colspan='2'>[[2qk5]] 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=2QK5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2QK5 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]] 2.2&#8491;</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=CS5:N-{(1S,2R)-1-(3,5-DIFLUOROBENZYL)-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-5-METHYL-N,N-DIPROPYLISOPHTHALAMIDE'>CS5</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=2qk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qk5 OCA], [https://pdbe.org/2qk5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2qk5 RCSB], [https://www.ebi.ac.uk/pdbsum/2qk5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2qk5 ProSAT]</span></td></tr>
|RELATEDENTRY=[[2qkj|2qkj]], [[2qmd|2qmd]], [[2qmf|2qmf]], [[2qmg|2qmg]], [[2qp8|2qp8]]
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2qk5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qk5 OCA], [http://www.ebi.ac.uk/pdbsum/2qk5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2qk5 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/qk/2qk5_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=2qk5 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 BACE1 bound to SCH626485'''
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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2qk5" 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/>
2QK5 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=2QK5 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 04:50:13 2008''

Latest revision as of 05:28, 17 October 2024

Structure of BACE1 bound to SCH626485

2qk5, resolution 2.20Å

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