{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Lantz C"],"funding":["National Institute of Neurological Disorders and Stroke","National Center for Research Resources","NIDCR NIH HHS","NCRR NIH HHS","National Institute of General Medical Sciences","Cure Sanfilippo Foundation","Office of the Director","Basic Energy Sciences","NINDS NIH HHS","National Institute of Dental and Craniofacial Research","Binder Family Foundation","NIGMS NIH HHS","NIH HHS"],"pagination":["2739-2747"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10959575"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["34(12)"],"pubmed_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"],"pubmed_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."],"pmcid":["PMC10959575"],"funding_grant_id":["RF1NS126406","S10RR028893","R01 GM103479","GM007185","R21NS130326","RF1 NS126406","S10OD018504","DE-FC02-02ER63421","R35GM145286","S10 OD018504","T90 DE030860","R21 NS130326","R35 GM145286","T32 GM007185","T90DE030860","R01GM103479","S10 RR028893"],"pubmed_authors":["Schrader T","Lopez J","Zenaidee MA","Biggs K","Loo JA","Lantz C","Bitan G","Whitelegge JP","Ogorzalek Loo RR","Klarner FG","Goring AK"],"additional_accession":[]},"is_claimable":false,"name":"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.","description":"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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Dec","modification":"2025-04-27T02:05:18.579Z","creation":"2025-04-06T18:31:34.424Z"},"accession":"S-EPMC10959575","cross_references":{"pubmed":["37936057"],"doi":["10.1021/jasms.3c00281"]}}