5HBT

Complex structure of Fab35 and human nAChR alpha1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 

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This is version 2.0 of the entry. See complete history


Literature

Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications.

Noridomi, K.Watanabe, G.Hansen, M.N.Han, G.W.Chen, L.

(2017) Elife 6

  • DOI: https://doi.org/10.7554/eLife.23043
  • Primary Citation of Related Structures:  
    5HBT, 5HBV

  • PubMed Abstract: 

    The nicotinic acetylcholine receptor (nAChR) is a major target of autoantibodies in myasthenia gravis (MG), an autoimmune disease that causes neuromuscular transmission dysfunction. Despite decades of research, the molecular mechanisms underlying MG have not been fully elucidated. Here, we present the crystal structure of the nAChR α1 subunit bound by the Fab fragment of mAb35, a reference monoclonal antibody that causes experimental MG and competes with ~65% of antibodies from MG patients. Our structures reveal for the first time the detailed molecular interactions between MG antibodies and a core region on nAChR α1. These structures suggest a major nAChR-binding mechanism shared by a large number of MG antibodies and the possibility to treat MG by blocking this binding mechanism. Structure-based modeling also provides insights into antibody-mediated nAChR cross-linking known to cause receptor degradation. Our studies establish a structural basis for further mechanistic studies and therapeutic development of MG.


  • Organizational Affiliation

    Department of Chemistry, University of Southern California, Los Angeles, United States.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholine receptor subunit alpha 1A [auth B]212Homo sapiensMutation(s): 3 
Gene Names: CHRNA1hCG_1811440
UniProt & NIH Common Fund Data Resources
Find proteins for P02708 (Homo sapiens)
Explore P02708 
Go to UniProtKB:  P02708
PHAROS:  P02708
GTEx:  ENSG00000138435 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP02708
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab35, Light ChainB [auth C]213Rattus norvegicusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Fab35, Heavy ChainC [auth D]219Rattus norvegicusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Alpha-bungarotoxin isoform V31D [auth A]74Bungarus multicinctusMutation(s): 0 
UniProt
Find proteins for P60616 (Bungarus multicinctus)
Explore P60616 
Go to UniProtKB:  P60616
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UniProt GroupP60616
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E
9N-Glycosylation
Glycosylation Resources
GlyTouCan:  G68668TB
GlyCosmos:  G68668TB
GlyGen:  G68668TB
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.260 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.210 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 160.006α = 90
b = 42.143β = 117.05
c = 136.488γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-03
    Type: Initial release
  • Version 1.1: 2017-05-10
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary