6MG4

Structure of full-length human lambda-6A light chain JTO


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report

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This is version 1.4 of the entry. See complete history


Literature

Stabilization of amyloidogenic immunoglobulin light chains by small molecules.

Morgan, G.J.Yan, N.L.Mortenson, D.E.Rennella, E.Blundon, J.M.Gwin, R.M.Lin, C.Y.Stanfield, R.L.Brown, S.J.Rosen, H.Spicer, T.P.Fernandez-Vega, V.Merlini, G.Kay, L.E.Wilson, I.A.Kelly, J.W.

(2019) Proc Natl Acad Sci U S A 116: 8360-8369

  • DOI: https://doi.org/10.1073/pnas.1817567116
  • Primary Citation of Related Structures:  
    6MG4, 6MG5

  • PubMed Abstract: 

    In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin. A protease-coupled fluorescence polarization-based high-throughput screen was employed to identify small molecules that kinetically stabilize LCs. NMR and X-ray crystallographic data demonstrate that at least one structural family of hits bind at the LC-LC dimerization interface within full-length LCs, utilizing variable-domain residues that are highly conserved in most AL patients. Stopping the amyloidogenesis cascade at the beginning is a proven strategy to ameliorate postmitotic tissue degeneration.


  • Organizational Affiliation

    Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; gjmorgan@bu.edu jkelly@scripps.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
JTO light chain
A, B
217Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.385α = 90
b = 82.464β = 90
c = 97.017γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Currently 6MG4 does not have a validation slider image.



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesDK46335

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-10
    Type: Initial release
  • Version 1.1: 2019-04-24
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-01
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-11
    Changes: Data collection, Database references, Refinement description