3VV6
Crystal Structure of beta secetase in complex with 2-amino-3-methyl-6-((1S, 2R)-2-phenylcyclopropyl)pyrimidin-4(3H)-one
Summary for 3VV6
| Entry DOI | 10.2210/pdb3vv6/pdb |
| Related | 3VV7 3VV8 |
| Descriptor | Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | aspartyl protease, bace, bata secretase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P56817 |
| Total number of polymer chains | 1 |
| Total formula weight | 47637.23 |
| Authors | Yonezawa, S.,Yamamoto, T.,Yamakawa, H.,Muto, C.,Hosono, M.,Hattori, K.,Higashino, K.,Sakagami, M.,Togame, H.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S. (deposition date: 2012-07-17, release date: 2012-10-24, Last modification date: 2024-11-13) |
| Primary citation | Yonezawa, S.,Yamamoto, T.,Yamakawa, H.,Muto, C.,Hosono, M.,Hattori, K.,Higashino, K.,Yutsudo, T.,Iwamoto, H.,Kondo, Y.,Sakagami, M.,Togame, H.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S. Conformational restriction approach to beta-secretase (BACE1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode J.Med.Chem., 55:8838-8858, 2012 Cited by PubMed Abstract: Improvement of a drug's binding activity using the conformational restriction approach with sp³ hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors. PubMed: 22998419DOI: 10.1021/jm3011405 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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