2f3f

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[[Image:2f3f.gif|left|200px]]
 
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{{Structure
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==Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor==
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|PDB= 2f3f |SIZE=350|CAPTION= <scene name='initialview01'>2f3f</scene>, resolution 2.300&Aring;
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<StructureSection load='2f3f' size='340' side='right'caption='[[2f3f]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=AXF:(2R,4S)-N-BUTYL-4-HYDROXY-2-METHYL-+4-((E)-(4AS,12R,15S,17AS)-15-METHYL+-14,17-DIOXO-2,3,4,4A,6,9,11,12,13,+14,15,16,17,17A-TETRADECAHYDRO-1H-5+,10-DITHIA-1,13,16-TRIAZA-BENZOCYCL+OPENTADECEN-12-YL)-BUTYRAMIDE'>AXF</scene>
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<table><tr><td colspan='2'>[[2f3f]] is a 3 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=2F3F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F3F FirstGlance]. <br>
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|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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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|GENE= BACE1, BACE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AXF:(2R,4S)-N-butyl-4-hydroxy-2-methyl-4-[(4aS,7E,12R,15S,17aS)-15-methyl-14,17-dioxo-2,3,4,4a,6,9,11,12,13,14,15,16,17,17a-tetradecahydro-1H-pyrido[2,3-i][1,11,4,7]dithiadiazacyclopentadecin-12-yl]butanamide'>AXF</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2f3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f3f OCA], [https://pdbe.org/2f3f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f3f RCSB], [https://www.ebi.ac.uk/pdbsum/2f3f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f3f ProSAT]</span></td></tr>
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|RELATEDENTRY=[[2f3e|2F3E]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2f3f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f3f OCA], [http://www.ebi.ac.uk/pdbsum/2f3f PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2f3f RCSB]</span>
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== Function ==
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}}
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f3/2f3f_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2f3f ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.
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'''Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor'''
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Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE).,Hanessian S, Yang G, Rondeau JM, Neumann U, Betschart C, Tintelnot-Blomley M J Med Chem. 2006 Jul 27;49(15):4544-67. PMID:16854060<ref>PMID:16854060</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2f3f" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were designed and synthesized. Analogues containing dithia, dioxa, oxathia, and carbathia macrocycles were synthesized by methods relying on ring-closing olefin metathesis for the dioxa analogues and by alkylation of thiolates or bisthiolates for the others. Molecular modeling suggested that the incorporation of piperidine units appended to the macrocycles improved interactions through additional H-bonds and introduced further rigidity. These were synthesized in enantiomerically pure form using enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was observed with several macroheterocyclic inhibitors and structure-activity relationship (SAR) correlations were deduced. Cocrystal structures of two synthetic analogues revealed interesting and unexpected binding interactions.
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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2F3F 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=2F3F OCA].
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__TOC__
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</StructureSection>
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==Reference==
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Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)., Hanessian S, Yang G, Rondeau JM, Neumann U, Betschart C, Tintelnot-Blomley M, J Med Chem. 2006 Jul 27;49(15):4544-67. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16854060 16854060]
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Memapsin 2]]
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[[Category: Large Structures]]
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[[Category: Single protein]]
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[[Category: Rondeau J-M]]
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[[Category: Rondeau, J M.]]
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[[Category: alzheimer's disease]]
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[[Category: aspartic protease]]
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[[Category: beta-secretase]]
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[[Category: macrocyclic peptidomimetic inhibitor]]
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[[Category: memapsin2]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:57:22 2008''
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Current revision

Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor

PDB ID 2f3f

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