4FGX

Crystal structure of bace1 with novel inhibitor

Summary for 4FGX

• Entry DOI: 10.2210/pdb4fgx/pdb
• Related: 4FCO
• Descriptor: Beta-secretase 1, Inhibitor (2R,5S,8S,12S,13S,16S,19S,22S)-16-(3-amino-3-oxopropyl)-2,13-dibenzyl-12,22-dihydroxy-8-isobutyl-19-isopropyl-3,5,17-trimethyl-4,7,10,15,18,21-hexaoxo-3,6,9,14,17,20-hexaazatricosan-1-oic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: hydrolase, 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: 2
• Total formula weight: 49545.31

Authors

Chen, T.T.,Chen, W.Y.,Li, L.,Xu, Y.C. (deposition date: 2012-06-05, release date: 2013-01-16, Last modification date: 2021-09-15)

Primary citation

Liu, Y.,Zhang, W.,Li, L.,Salvador, L.A.,Chen, T.,Chen, W.,Felsenstein, K.M.,Ladd, T.B.,Price, A.R.,Golde, T.E.,He, J.,Xu, Y.,Li, Y.,Luesch, H.
Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
J.Med.Chem., 55:10749-10765, 2012

PubMed Abstract: Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPPβ), membrane bound carboxyl terminal fragment (CTF), levels of β-amyloid (Aβ) peptides and selectivity for β-secretase (BACE1) over γ-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Aβ levels in the rodent brain.

PubMed: 23181502
DOI: 10.1021/jm301630s

Experimental method

X-RAY DIFFRACTION (1.59 Å)