6NCO

Fragment-based Discovery of an apoE4 Stabilizer

Summary for 6NCO

• Entry DOI: 10.2210/pdb6nco/pdb
• Descriptor: Apolipoprotein E, 1-[5-chloro-4'-(2-hydroxypropan-2-yl)[1,1'-biphenyl]-3-yl]cyclobutane-1-carboximidamide (3 entities in total)
• Functional Keywords: lipid binding, lipid transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 21866.08

Authors

Jakob, C.G.,Qiu, W. (deposition date: 2018-12-11, release date: 2019-04-17, Last modification date: 2023-10-11)

Primary citation

Petros, A.M.,Korepanova, A.,Jakob, C.G.,Qiu, W.,Panchal, S.C.,Wang, J.,Dietrich, J.D.,Brewer, J.T.,Pohlki, F.,Kling, A.,Wilcox, K.,Lakics, V.,Bahnassawy, L.,Reinhardt, P.,Partha, S.K.,Bodelle, P.M.,Lake, M.,Charych, E.I.,Stoll, V.S.,Sun, C.,Mohler, E.G.
Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer.
J.Med.Chem., 62:4120-4130, 2019

PubMed Abstract: Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.

PubMed: 30933499
DOI: 10.1021/acs.jmedchem.9b00178

Experimental method

X-RAY DIFFRACTION (1.707 Å)