3WB5

Crystal Structure of beta secetase in complex with (6S)-2-amino-3,6-dimethyl-6-[(1R,2R)-2-phenylcyclopropyl]-3,4,5,6-tetrahydropyrimidin-4-one

Summary for 3WB5

• Entry DOI: 10.2210/pdb3wb5/pdb
• Related: 3WB4
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: protease 2, asp2, membrane-associated aspartic protease 2, memapsin-2, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 47293.41

Authors

Yonezawa, S.,Fujiwara, K.,Yamamoto, T.,Hattori, K.,Yamakawa, H.,Muto, C.,Hosono, M.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S. (deposition date: 2013-05-13, release date: 2013-10-02, Last modification date: 2024-11-20)

Primary citation

Yonezawa, S.,Fujiwara, K.,Yamamoto, T.,Hattori, K.,Yamakawa, H.,Muto, C.,Hosono, M.,Tanaka, Y.,Nakano, T.,Takemoto, H.,Arisawa, M.,Shuto, S.
Conformational restriction approach to beta-secretase (BACE1) inhibitors III: Effective investigation of the binding mode by combinational use of X-ray analysis, isothermal titration calorimetry and theoretical calculations
Bioorg.Med.Chem., 21:6506-6522, 2013

PubMed Abstract: For further investigation of BACE1 inhibitors using conformational restriction with sp(3) hybridized carbon, we applied this approach to 6-substituted aminopyrimidone derivatives 3 to improve the inhibitory activity by reducing the entropic energy loss upon binding to BACE1. Among eight stereoisomers synthesized, [trans-(1'R,2'R),6S] isomer 6 exhibited the best BACE1 inhibitory activity, which was statistically superior to that of the corresponding ethylene linker compound (R)-3. Combinational examinations of the binding mode of 6 were performed, which included isothermal titration calorimetry (ITC), X-ray crystallographic structure analysis and theoretical calculations, to clarify the effect of our conformational restriction approach. From the ITC measurement, the binding entropy of 6 was found to be ∼0.5kcal larger than that of (R)-3, which is considered to be affected by conformational restriction with a cyclopropane ring.

PubMed: 24051074
DOI: 10.1016/j.bmc.2013.08.036

Experimental method

X-RAY DIFFRACTION (2.501 Å)