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[[Image:1xn2.gif|left|200px]]
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{{STRUCTURE_1xn2|  PDB=1xn2  |  SCENE=  }}
'''New substrate binding pockets for beta-secretase.'''


==New substrate binding pockets for beta-secretase.==
<StructureSection load='1xn2' size='340' side='right'caption='[[1xn2]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1xn2]] is a 8 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=1XN2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XN2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1OL:(2R,4S,5S)-5-AMINO-4-HYDROXY-2,7-DIMETHYLOCTANOIC+ACID'>1OL</scene></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=1xn2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xn2 OCA], [https://pdbe.org/1xn2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xn2 RCSB], [https://www.ebi.ac.uk/pdbsum/1xn2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xn2 ProSAT]</span></td></tr>
</table>
== 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/xn/1xn2_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=1xn2 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the pathogenesis of Alzheimer's disease. The active site of memapsin 2 has been shown, with kinetic data and crystal structures, to bind to eight substrate residues (P(4)-P(4)'). We describe here that the addition of three substrate residues from P(7) to P(5) strongly influences the hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic residues, especially tryptophan. A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues. Kinetic studies revealed that the addition of these substrate residues contributes to the decrease in K(m) and increase in k(cat) values, suggesting that these residues contribute to both substrate recognition and transition-state binding. The crystal structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2 revealed the interaction of a tryptophan with the S(6) subsite of the protease.


==Overview==
Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase).,Turner RT 3rd, Hong L, Koelsch G, Ghosh AK, Tang J Biochemistry. 2005 Jan 11;44(1):105-12. PMID:15628850<ref>PMID:15628850</ref>
Memapsin 2 (beta-secretase) is the membrane-anchored aspartic protease that initiates the cleavage of beta-amyloid precursor protein (APP), leading to the production of amyloid-beta (Abeta), a major factor in the pathogenesis of Alzheimer's disease. The active site of memapsin 2 has been shown, with kinetic data and crystal structures, to bind to eight substrate residues (P(4)-P(4)'). We describe here that the addition of three substrate residues from P(7) to P(5) strongly influences the hydrolytic activity by memapsin 2 and these subsites prefer hydrophobic residues, especially tryptophan. A crystal structure of memapsin 2 complexed with a statine-based inhibitor spanning P(10)-P(4)' revealed the binding positions of P(5)-P(7) residues. Kinetic studies revealed that the addition of these substrate residues contributes to the decrease in K(m) and increase in k(cat) values, suggesting that these residues contribute to both substrate recognition and transition-state binding. The crystal structure of a new inhibitor, OM03-4 (K(i) = 0.03 nM), bound to memapsin 2 revealed the interaction of a tryptophan with the S(6) subsite of the protease.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1XN2 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=1XN2 OCA].
</div>
<div class="pdbe-citations 1xn2" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
Structural locations and functional roles of new subsites S5, S6, and S7 in memapsin 2 (beta-secretase)., Turner RT 3rd, Hong L, Koelsch G, Ghosh AK, Tang J, Biochemistry. 2005 Jan 11;44(1):105-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15628850 15628850]
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Ghosh AK]]
[[Category: Ghosh, A K.]]
[[Category: Hong L]]
[[Category: Hong, L.]]
[[Category: Koelsch G]]
[[Category: III, R T.Turner.]]
[[Category: Tang J]]
[[Category: Koelsch, G.]]
[[Category: Turner III RT]]
[[Category: Tang, J.]]
[[Category: Alzheimer's disease]]
[[Category: Asp2]]
[[Category: Aspartic protease]]
[[Category: Bace]]
[[Category: Beta secretase]]
[[Category: Drug design.]]
[[Category: Memapsin2]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 15:14:46 2008''
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