Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules

Abstract

The fibrillary aggregation of the protein alpha synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small molecule binding sites on fibrils is essential to the development of diagnostic imaging probes. A series of molecular modeling, photoaffinity labeling, mass spectrometry, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of three different binding sites within fibrillar Asyn capable of binding small molecules with moderate to high affinity. A knowledge of the amino acid residues in these binding sites will be important in the design of high affinity probes capable of imaging fibrillary species of Asyn.

Nonantioxidant Tetramethoxystilbene Abrogates α-Synuclein-Induced Yeast Cell Death but Not That Triggered by the Bax or βA4 Peptide

“…Preclinical studies have shown that the α-syn fibrils cause Parkinson-like neurodegeneration in nontransgenic mice models. 29 Furthermore, recently Mach and co-workers 30 have shown that small molecules binds to various pockets of the β-sheet structure (residue K34 to K97) of α-syn fibrils which is rich in hydrophobic residues; thus it was speculated that methoxystilbenes would display strong interactions with the β-sheet structure. Thus, a series of mono-, di-, tri-, and tetramethoxy-stilbenes were synthesized as depicted in Figure 1B.…”

Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins

“…Finally, docking of potential ligands can be done to the structure of the already formed α-synuclein fibrils, which have a few potential binding sites for small molecules in the β-structured NAC-domain and unstructured tails of the polypeptide chain [ 117 ] ( Figure 4 b). This approach seems appropriate for the compounds that are expected to bind not to monomeric, but oligomeric forms or formed fibrils of α-synuclein, and potentially influence their assembly rate or disintegrate them.…”

“…Blue, red, green, and grey represent basic, acidic, polar, and hydrophobic residues respectively. For the details about the “hotspot” region of PrP (1), see the details in the text; the binding sites localization on α-synuclein fibrils is based on data from [ 117 , 118 ].…”

Dammarane triterpenes targeting α-synuclein: biological activity and evaluation of binding sites by molecular docking

“…This model contains 10 units of the peptide (140 amino acids), which are arranged in parallel by presenting features that commonly stabilise amyloid folds (such as intermolecular salt bridge, a glutamine ladder, steric zippers involving hydrophobic residues, and in-register parallel-b-sheet hydrogen-bonding with a Greek key motif). In a recent report, Hsieh et al used this structure as a target protein for molecular blind docking of small molecules 21 . They found 13 putative binding sites, but they excluded a number of these sites based on their low percent probability of interaction; finally, they identified site 2 (with residues Y39, S42, and T44), site 9 (with residues G86, F94, and K96), and the site 3/13 (with residues L43, L45, V48, and H50) 21 .…”

“…In a recent report, Hsieh et al used this structure as a target protein for molecular blind docking of small molecules 21 . They found 13 putative binding sites, but they excluded a number of these sites based on their low percent probability of interaction; finally, they identified site 2 (with residues Y39, S42, and T44), site 9 (with residues G86, F94, and K96), and the site 3/13 (with residues L43, L45, V48, and H50) 21 . Docking calculations were executed inside these sites by using Glide XP method 22 .…”