3R1G

Structure Basis of Allosteric Inhibition of BACE1 by an Exosite-Binding Antibody

Summary for 3R1G

• Entry DOI: 10.2210/pdb3r1g/pdb
• Descriptor: Beta-secretase 1, FAB of YW412.8.31 antibody heavy chain, FAB of YW412.8.31 antibody light chain, ... (4 entities in total)
• Functional Keywords: aspartal protease, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 91285.18

Authors

Wang, W.,Rouge, L.,Wu, P.,Chiu, C.,Chen, Y.,Wu, Y.,Watts, R.J. (deposition date: 2011-03-10, release date: 2011-06-08, Last modification date: 2024-11-27)

Primary citation

Atwal, J.K.,Chen, Y.,Chiu, C.,Mortensen, D.L.,Meilandt, W.J.,Liu, Y.,Heise, C.E.,Hoyte, K.,Luk, W.,Lu, Y.,Peng, K.,Wu, P.,Rouge, L.,Zhang, Y.,Lazarus, R.A.,Scearce-Levie, K.,Wang, W.,Wu, Y.,Tessier-Lavigne, M.,Watts, R.J.
A Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-{beta} Production in Vivo.
Sci Transl Med, 3:84ra43-84ra43, 2011

PubMed Abstract: Reducing production of amyloid-β (Aβ) peptide by direct inhibition of the enzymes that process amyloid precursor protein (APP) is a central therapeutic strategy for treating Alzheimer's disease. However, small-molecule inhibitors of the β-secretase (BACE1) and γ-secretase APP processing enzymes have shown a lack of target selectivity and poor penetrance of the blood-brain barrier (BBB). Here, we have developed a high-affinity, phage-derived human antibody that targets BACE1 (anti-BACE1) and is anti-amyloidogenic. Anti-BACE1 reduces endogenous BACE1 activity and Aβ production in human cell lines expressing APP and in cultured primary neurons. Anti-BACE1 is highly selective and does not inhibit the related enzymes BACE2 or cathepsin D. Competitive binding assays and x-ray crystallography indicate that anti-BACE1 binds noncompetitively to an exosite on BACE1 and not to the catalytic site. Systemic dosing of mice and nonhuman primates with anti-BACE1 resulted in sustained reductions in peripheral Aβ peptide concentrations. Anti-BACE1 also reduces central nervous system Aβ concentrations in mouse and monkey, consistent with a measurable uptake of antibody across the BBB. Thus, BACE1 can be targeted in a highly selective manner through passive immunization with anti-BACE1, providing a potential approach for treating Alzheimer's disease. Nevertheless, therapeutic success with anti-BACE1 will depend on improving antibody uptake into the brain.

PubMed: 21613622
DOI: 10.1126/scitranslmed.3002254

Experimental method

X-RAY DIFFRACTION (2.8 Å)