{"doi":"10.1021/jasms.3c00281","title":"Characterization of Molecular Tweezer Binding on α-Synuclein with Native Top-Down Mass Spectrometry and Ion Mobility-Mass Spectrometry Reveals a Mechanism for Aggregation Inhibition","abstract":"Parkinson's disease, a neurodegenerative disease that affects 15 million people worldwide, is characterized by deposition of α-synuclein into Lewy Bodies in brain neurons. Although this disease is prevalent worldwide, a therapy or cure has yet to be found. Several small compounds have been reported to disrupt fibril formation. Among these compounds is a molecular tweezer known as CLR01 that targets lysine and arginine residues. This study aims to characterize how CLR01 interacts with various proteoforms of α-synuclein and how the structure of α-synuclein is subsequently altered. Native mass spectrometry (nMS) measurements of α-synuclein/CLR01 complexes reveal that multiple CLR01 molecules can bind to α-synuclein proteoforms such as α-synuclein phosphorylated at Ser-129 and α-synuclein bound with copper and manganese ions. The binding of one CLR01 molecule shifts the ability for α-synuclein to bind other ligands. Electron capture dissociation (ECD) with Fourier transform-ion cyclotron resonance (FT-ICR) top-down (TD) mass spectrometry of α-synuclein/CLR01 complexes pinpoints the locations of the modifications on each proteoform and reveals that CLR01 binds to the N-terminal region of α-synuclein. CLR01 binding compacts the gas-phase structure of α-synuclein, as shown by ion mobility-mass spectrometry (IM-MS). These data suggest that when multiple CLR01 molecules bind, the N-terminus of α-synuclein shifts toward a more compact state. This compaction suggests a mechanism for CLR01 halting the formation of oligomers and fibrils involved in many neurodegenerative diseases.","journal":"Journal of the American Society for Mass Spectrometry","year":2023,"id":345266,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1085254,"name":"Jaybree Lopez","orcid":null,"position":1,"is_corresponding":false},{"id":576004,"name":"Andrew K. Goring","orcid":"0000-0003-4220-6472","position":2,"is_corresponding":false},{"id":590010,"name":"Muhammad A. Zenaidee","orcid":"0000-0003-3188-1472","position":3,"is_corresponding":false},{"id":847206,"name":"Karl Biggs","orcid":null,"position":4,"is_corresponding":false},{"id":244624,"name":"Julian P. Whitelegge","orcid":"0000-0003-2763-7733","position":5,"is_corresponding":false},{"id":373692,"name":"Rachel R. Ogorzalek Loo","orcid":"0000-0002-0580-2833","position":6,"is_corresponding":false},{"id":299944,"name":"Frank‐Gerrit Klärner","orcid":null,"position":7,"is_corresponding":false},{"id":297527,"name":"Thomas Schräder","orcid":"0000-0002-7003-6362","position":8,"is_corresponding":false},{"id":240762,"name":"Gal Bitan","orcid":"0000-0001-7046-3754","position":9,"is_corresponding":false},{"id":256466,"name":"Joseph A. Loo","orcid":"0000-0001-9989-1437","position":10,"is_corresponding":false},{"id":257355,"name":"Carter Lantz","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:11:39.484741Z","pmid":"37936057","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}