2OHM
X-ray crystal structure of beta secretase complexed with N~3~-benzylpyridine-2,3-diamine
Summary for 2OHM
| Entry DOI | 10.2210/pdb2ohm/pdb |
| Related | 2OF0 2OHK 2OHL 2OHN 2OHP 2OHQ 2OHR 2OHS 2OHT 2OHU |
| Descriptor | Beta-secretase 1, IODIDE ION, DIMETHYL SULFOXIDE, ... (5 entities in total) |
| Functional Keywords | alternative splicing, alzheimer's disease, aspartic protease, aspartyl protease, base, beta-secretase, glycoprotein, hydrolase, memapsin 2, transmembrane, zymogen |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 1 |
| Total formula weight | 45372.59 |
| Authors | Patel, S. (deposition date: 2007-01-10, release date: 2007-03-13, Last modification date: 2024-10-30) |
| Primary citation | Murray, C.W.,Callaghan, O.,Chessari, G.,Cleasby, A.,Congreve, M.,Frederickson, M.,Hartshorn, M.J.,McMenamin, R.,Patel, S.,Wallis, N. Application of fragment screening by X-ray crystallography to beta-Secretase. J.Med.Chem., 50:1116-1123, 2007 Cited by PubMed Abstract: 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. PubMed: 17315856DOI: 10.1021/jm0611962 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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