4LAS

Crystal structure of a therapeutic single chain antibody in complex with 4-hydroxymethamphetamine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.164 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites.

Peterson, E.C.Celikel, R.Gokulan, K.Varughese, K.I.

(2013) PLoS One 8: e82690-e82690

  • DOI: https://doi.org/10.1371/journal.pone.0082690
  • Primary Citation of Related Structures:  
    4LAQ, 4LAR, 4LAS

  • PubMed Abstract: 

    Vaccines and monoclonal antibodies (mAb) for treatment of (+)-methamphetamine (METH) abuse are in late stage preclinical and early clinical trial phases, respectively. These immunotherapies work as pharmacokinetic antagonists, sequestering METH and its metabolites away from sites of action in the brain and reduce the rewarding and toxic effects of the drug. A key aspect of these immunotherapy strategies is the understanding of the subtle molecular interactions important for generating antibodies with high affinity and specificity for METH. We previously determined crystal structures of a high affinity anti-METH therapeutic single chain antibody fragment (scFv6H4, K(D) = 10 nM) in complex with METH and the (+) stereoisomer of 3,4-methylenedioxymethamphetamine (MDMA, or "ecstasy"). Here we report the crystal structure of scFv6H4 in homo-trimeric unbound (apo) form (2.60Å), as well as monomeric forms in complex with two active metabolites; (+)-amphetamine (AMP, 2.38Å) and (+)-4-hydroxy methamphetamine (p-OH-METH, 2.33Å). The apo structure forms a trimer in the crystal lattice and it results in the formation of an intermolecular composite beta-sheet with a three-fold symmetry. We were also able to structurally characterize the coordination of the His-tags with Ni(2+). Two of the histidine residues of each C-terminal His-tag interact with Ni(2+) in an octahedral geometry. In the apo state the CDR loops of scFv6H4 form an open conformation of the binding pocket. Upon ligand binding, the CDR loops adopt a closed formation, encasing the drug almost completely. The structural information reported here elucidates key molecular interactions important in anti-methamphetamine abuse immunotherapy.


  • Organizational Affiliation

    Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Single chain antibody fragment scFv6H4A [auth H]249Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1WF
Query on 1WF

Download Ideal Coordinates CCD File 
B [auth H]4-[(2S)-2-(methylamino)propyl]phenol
C10 H15 N O
SBUQZKJEOOQSBV-QMMMGPOBSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.33 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.164 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 34.279α = 90
b = 65.297β = 98.36
c = 48.574γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CNSrefinement
HKL-2000data collection
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-12-11
    Type: Initial release
  • Version 1.1: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 2.0: 2019-12-25
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Polymer sequence, Source and taxonomy, Structure summary
  • Version 2.1: 2024-10-30
    Changes: Data collection, Database references, Derived calculations, Structure summary