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| - | [[Image:2ohl.gif|left|200px]] | |
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| - | {{Structure
| + | ==X-ray crystal structure of beta secretase complexed with 2-aminoquinoline== |
| - | |PDB= 2ohl |SIZE=350|CAPTION= <scene name='initialview01'>2ohl</scene>, resolution 2.650Å
| + | <StructureSection load='2ohl' size='340' side='right'caption='[[2ohl]], [[Resolution|resolution]] 2.65Å' scene=''> |
| - | |SITE=
| + | == Structural highlights == |
| - | |LIGAND= <scene name='pdbligand=2AQ:QUINOLIN-2-AMINE'>2AQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene> | + | <table><tr><td colspan='2'>[[2ohl]] 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=2OHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2OHL 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]] 2.65Å</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=2AQ:QUINOLIN-2-AMINE'>2AQ</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=2ohl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ohl OCA], [https://pdbe.org/2ohl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ohl RCSB], [https://www.ebi.ac.uk/pdbsum/2ohl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ohl ProSAT]</span></td></tr> |
| - | |RELATEDENTRY=[[2of0|2OF0]], [[2ohk|2OHK]], [[2ohm|2OHM]], [[2ohn|2OHN]], [[2ohp|2OHP]], [[2ohq|2OHQ]], [[2ohr|2OHR]], [[2ohs|2OHS]], [[2oht|2OHT]], [[2ohu|2OHU]]
| + | </table> |
| - | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ohl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ohl OCA], [http://www.ebi.ac.uk/pdbsum/2ohl PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2ohl 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/oh/2ohl_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=2ohl ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment. |
| | | | |
| - | '''X-ray crystal structure of beta secretase complexed with 2-aminoquinoline'''
| + | Application of fragment screening by X-ray crystallography to beta-secretase.,Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:17315856<ref>PMID:17315856</ref> |
| | | | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 2ohl" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Overview== | + | ==See Also== |
| - | This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.
| + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure==
| + | <references/> |
| - | 2OHL 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=2OHL OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference== | + | |
| - | Application of fragment screening by X-ray crystallography to beta-secretase., Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N, J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17315856 17315856]
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Single protein]]
| + | [[Category: Patel S]] |
| - | [[Category: Patel, S.]] | + | |
| - | [[Category: alternative splicing]]
| + | |
| - | [[Category: alzheimer's disease]]
| + | |
| - | [[Category: aspartic protease]]
| + | |
| - | [[Category: aspartyl protease]]
| + | |
| - | [[Category: base]]
| + | |
| - | [[Category: beta-secretase]]
| + | |
| - | [[Category: glycoprotein]]
| + | |
| - | [[Category: hydrolase]]
| + | |
| - | [[Category: memapsin 2]]
| + | |
| - | [[Category: signal]]
| + | |
| - | [[Category: transmembrane]]
| + | |
| - | [[Category: zymogen]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:17:59 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
This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment.
Application of fragment screening by X-ray crystallography to beta-secretase.,Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:17315856[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
- ↑ Murray CW, Callaghan O, Chessari G, Cleasby A, Congreve M, Frederickson M, Hartshorn MJ, McMenamin R, Patel S, Wallis N. Application of fragment screening by X-ray crystallography to beta-secretase. J Med Chem. 2007 Mar 22;50(6):1116-23. Epub 2007 Feb 22. PMID:17315856 doi:http://dx.doi.org/10.1021/jm0611962
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