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The immunological evolution of catalysis

Academic Article
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Overview

authors

  • Patten, P. A.
  • Gray, N. S.
  • Yang, P. L.
  • Marks, C. B.
  • Wedemayer, G. J.
  • Boniface, J. J.
  • Stevens, Raymond
  • Schultz, Peter

publication date

  • February 1996

journal

  • Science  Journal

abstract

  • The germline genes used by the mouse to generate the esterolytic antibody 48G7 were cloned and expressed in an effort to increase our understanding of the detailed molecular mechanisms by which the immune system evolves catalytic function. The nine replacement mutations that were fixed during affinity maturation increased affinity for the transition state analogue by a factor of 10(4), primarily the result of a decrease in the dissociation rate of the hapten-antibody complex. There was a corresponding increase in the rate of reaction of antibody with substrate, k(cat)/k(m), from 1.7 x 10(2)M(-1) min(-1) to 1.4 x 10(4)M(-1) min(-1). The three-dimensional crystal structure of the 48G7-transition state analogue complex at 2.0 angstroms resolution indicates that one of the nine residues in which somatic mutations have been fixed directly contact the hapten. Thus, in the case of 48G7, affinity maturation appears to play a conformational role, either in reorganizing the active site geometry of limiting side-chain and backbone flexibility of the germline antibody. The crystal structure and analysis of somatic and directed active site mutants underscore the role of transition state stabilization in the evolution of this catalytic antibody.

subject areas

  • Amino Acid Sequence
  • Animals
  • Antibodies, Catalytic
  • Antibody Affinity
  • Antigen-Antibody Complex
  • Antigen-Antibody Reactions
  • Base Sequence
  • Binding Sites
  • Catalysis
  • Cloning, Molecular
  • Crystallization
  • Crystallography, X-Ray
  • Evolution, Molecular
  • Genes, Immunoglobulin
  • Haptens
  • Immunoglobulin Fab Fragments
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
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Identity

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.271.5252.1086

PubMed ID

  • 8599084
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Additional Document Info

start page

  • 1086

end page

  • 1091

volume

  • 271

issue

  • 5252

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