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[[Image:1xs7.gif|left|200px]]


{{Structure
==Crystal Structure of a cycloamide-urethane-derived novel inhibitor bound to human brain memapsin 2 (beta-secretase).==
|PDB= 1xs7 |SIZE=350|CAPTION= <scene name='initialview01'>1xs7</scene>, resolution 2.8&Aring;
<StructureSection load='1xs7' size='340' side='right'caption='[[1xs7]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
|SITE=  
== Structural highlights ==
|LIGAND= <scene name='pdbligand=MMI:N-[(4S,5S,7R)-8-({(S)-1-[(BENZYLAMINO)OXOMETHYL]-2-METHYLPROPYL}AMINO)-5-HYDROXY-2,7-DIMETHYL-8-OXO-OCT-4-YL]-(4S,7S)-4-ISOPROPYL-2,5,9-TRIOXO-1-OXA-3,6,10-TRIAZACYCLOHEXADECANE-7-CARBOXAMIDE'>MMI</scene>
<table><tr><td colspan='2'>[[1xs7]] 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=1XS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XS7 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]] 2.8&#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=MMI:N-[(4S,5S,7R)-8-({(S)-1-[(BENZYLAMINO)OXOMETHYL]-2-METHYLPROPYL}AMINO)-5-HYDROXY-2,7-DIMETHYL-8-OXO-OCT-4-YL]-(4S,7S)-4-ISOPROPYL-2,5,9-TRIOXO-1-OXA-3,6,10-TRIAZACYCLOHEXADECANE-7-CARBOXAMIDE'>MMI</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=1xs7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xs7 OCA], [https://pdbe.org/1xs7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xs7 RCSB], [https://www.ebi.ac.uk/pdbsum/1xs7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xs7 ProSAT]</span></td></tr>
|RELATEDENTRY=
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1xs7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xs7 OCA], [http://www.ebi.ac.uk/pdbsum/1xs7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1xs7 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/xs/1xs7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1xs7 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A series of novel macrocyclic amide-urethanes was designed and synthesized based upon the X-ray crystal structure of our lead inhibitor (1, OM99-2 with eight residues) bound to memapsin 2. Ring size and substituent effects have been investigated. Cycloamide-urethanes containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against human brain memapsin 2 (beta-secretase).


'''Crystal Structure of a cycloamide-urethane-derived novel inhibitor bound to human brain memapsin 2 (beta-secretase).'''
Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (beta-secretase).,Ghosh AK, Devasamudram T, Hong L, DeZutter C, Xu X, Weerasena V, Koelsch G, Bilcer G, Tang J Bioorg Med Chem Lett. 2005 Jan 3;15(1):15-20. PMID:15582402<ref>PMID:15582402</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1xs7" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
A series of novel macrocyclic amide-urethanes was designed and synthesized based upon the X-ray crystal structure of our lead inhibitor (1, OM99-2 with eight residues) bound to memapsin 2. Ring size and substituent effects have been investigated. Cycloamide-urethanes containing 14- to 16-membered rings exhibited low nanomolar inhibitory potencies against human brain memapsin 2 (beta-secretase).
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 
== References ==
==About this Structure==
<references/>
1XS7 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=1XS7 OCA].
__TOC__
 
</StructureSection>
==Reference==
Structure-based design of cycloamide-urethane-derived novel inhibitors of human brain memapsin 2 (beta-secretase)., Ghosh AK, Devasamudram T, Hong L, DeZutter C, Xu X, Weerasena V, Koelsch G, Bilcer G, Tang J, Bioorg Med Chem Lett. 2005 Jan 3;15(1):15-20. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15582402 15582402]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Bilcer G]]
[[Category: Bilcer, G.]]
[[Category: DeZutter C]]
[[Category: DeZutter, C.]]
[[Category: Devasamudram T]]
[[Category: Devasamudram, T.]]
[[Category: Ghosh A]]
[[Category: Ghosh, A.]]
[[Category: Hong L]]
[[Category: Hong, L.]]
[[Category: Koelsch G]]
[[Category: Koelsch, G.]]
[[Category: Tang J]]
[[Category: Tang, J.]]
[[Category: Weerasena V]]
[[Category: Weerasena, V.]]
[[Category: Xu X]]
[[Category: Xu, X.]]
[[Category: acid protease]]
[[Category: alzheimer's disease]]
[[Category: asp2]]
[[Category: aspartic protease]]
[[Category: bace]]
[[Category: beta secretase]]
[[Category: crystallography]]
[[Category: drug design]]
[[Category: memapsin2]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:53:57 2008''

Latest revision as of 06:48, 23 August 2023

Crystal Structure of a cycloamide-urethane-derived novel inhibitor bound to human brain memapsin 2 (beta-secretase).

1xs7, resolution 2.80Å

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