Structural basis for a disfavored elimination reaction in catalytic antibody 1D4

J Mol Biol. 2001 Nov 16;314(1):93-102. doi: 10.1006/jmbi.2001.5112.

Abstract

Murine antibody 1D4 selectively catalyzes a highly disfavored beta-elimination reaction. Crystal structures of unliganded 1D4 and 1D4 in complex with a transition-state analog (TSA) have elucidated a possible general base mode of catalysis. The structures of the unliganded and liganded Fabs were determined to 1.80 and 1.85 A resolution, respectively. The structure of the complex reveals a binding pocket with high shape complementarity to the TSA, which is recruited to coerce the substrate into the sterically demanding, eclipsed conformation that is required for catalysis. A histidine residue and two water molecules are likely involved in the catalysis. The structure supports either a concerted E2 or stepwise E1cB-like mechanism for elimination. Finally, the liganded 1D4 structure shows minor conformational rearrangements in CDR H2, indicative of induced-fit binding of the hapten. 1D4 has pushed the boundaries of antibody-mediated catalysis into the realm of disfavored reactions and, hence, represents an important milestone in the development of this technology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Catalytic / chemistry*
  • Antibodies, Catalytic / immunology
  • Antibodies, Catalytic / metabolism*
  • Binding Sites, Antibody
  • Catalysis
  • Cations / metabolism
  • Crystallography, X-Ray
  • Entropy
  • Haptens / chemistry
  • Haptens / immunology
  • Haptens / metabolism
  • Hydrogen Bonding
  • Immunoglobulin Fab Fragments / chemistry*
  • Immunoglobulin Fab Fragments / immunology
  • Immunoglobulin Fab Fragments / metabolism*
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Ligands
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Solvents
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Antibodies, Catalytic
  • Cations
  • Haptens
  • Immunoglobulin Fab Fragments
  • Immunoglobulin G
  • Ligands
  • Solvents

Associated data

  • PDB/1JGU
  • PDB/1JGV