PXD068745

PXD068745 is an original dataset announced via ProteomeXchange.

Title	Stabilization of diverse amyloidogenic antibody light chains by small molecules revealed by hydrogen-deuterium exchange mass spectrometry
Description	Antibody light chains can aggregate as amyloid fibrils to cause systemic AL amyloidosis. Amyloid deposition requires unfolding of the light chain from its native state, but the mechanistic details of how this occurs are not fully understood. Inhibiting amyloid formation by stabilizing the precursor light chain proteins against unfolding and proteolysis is a potential therapeutic strategy. Small molecules that bind to the native state of light chains are under development as drug candidates. An important challenge for potential stabilizer drugs is to bind multiple light chains and suppress their dynamics, since every patient has a unique amyloid-forming light chain. Here, we used hydrogen-deuterium exchange measured by mass spectrometry to characterize the binding of six small molecule stabilizers to eleven different λ light chain proteins. Despite structural and dynamic differences among the light chains, the binding of the most efficacious stabilizer molecule led to increased protection from hydrogen exchange, consistent with reduced local and global unfolding. Protection upon binding was most prominent in residues within complementarity determining region 3 and framework region 4 of the light chain variable domains, which undergo major conformational changes upon amyloid formation. Stabilizer binding also reduced the rate at which all light chains were cleaved by protease. These data show how stabilizers can suppress the range of conformational dynamics associated with light chain aggregation, supporting their therapeutic potential.
HostingRepository	PRIDE
AnnounceDate	2026-07-27
AnnouncementXML	Submission_2026-07-27_06:06:21.005.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daniele Peterle
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-23 12:03:46	ID requested
⏵ 1	2026-07-27 06:06:21	announced

10.1016/j.jmb.2026.169917;

Peterle D, Yan NL, Klimtchuk ES, Srinivasu BY, Brusic V, Rhoades D, Wales TE, Gursky O, Kelly JW, Engen JR, Morgan GJ, Small Molecule Stabilization of Diverse Amyloidogenic Immunoglobulin Light Chains Revealed by Hydrogen-Deuterium Exchange Mass Spectrometry. J Mol Biol, 438(19):169917(2026) [pubmed]

submitter keyword: None

Thomas Wales
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA
contact email	T.Wales@northeastern.edu
lab head
Daniele Peterle
contact affiliation	Peptone Switzerland AG
contact email	d.peterle90@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/07/PXD068745

PRIDE project URI

• PRIDE
  1. PXD068745
     1. Label: PRIDE project
     2. Name: Stabilization of diverse amyloidogenic antibody light chains by small molecules revealed by hydrogen-deuterium exchange mass spectrometry