2F3F
Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor
Summary for 2F3F
| Entry DOI | 10.2210/pdb2f3f/pdb |
| Related | 2F3E |
| Descriptor | Beta-secretase 1, (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 (3 entities in total) |
| Functional Keywords | beta-secretase, memapsin2, alzheimer's disease, aspartic protease, macrocyclic peptidomimetic inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 3 |
| Total formula weight | 135876.24 |
| Authors | Rondeau, J.-M. (deposition date: 2005-11-21, release date: 2006-09-05, Last modification date: 2024-10-16) |
| Primary citation | Hanessian, S.,Yang, G.,Rondeau, J.-M.,Neumann, U.,Betschart, C.,Tintelnot-Blomley, M. Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE). J.Med.Chem., 49:4544-4567, 2006 Cited by PubMed Abstract: 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. PubMed: 16854060DOI: 10.1021/jm060154a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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