Document Detail

The interplay between binding energy and catalysis in the evolution of a catalytic antibody.
MedLine Citation:
PMID:  9305839     Owner:  NLM     Status:  MEDLINE    
Antibody catalysis provides an opportunity to examine the evolution of binding energy and its relation to catalytic function in a system that has many parallels with natural enzymes. Here we report such a study involving an antibody AZ-28 that catalyses an oxy-Cope rearrangement, a pericyclic reaction that belongs to a well studied and widely used class of reactions in organic chemistry. Immunization with transition state analogue 1 results in a germline-encoded antibody that catalyses the rearrangement of hexadiene 2 to aldehyde 3 with a rate approaching that of a related pericyclic reaction catalysed by the enzyme chorismate mutase. Affinity maturation gives antibody AZ-28, which has six amino acid substitutions, one of which results in a decrease in catalytic rate. To understand the relationship between binding and catalytic rate in this system we characterized a series of active-site mutants and determined the three-dimensional crystal structure of the complex of AZ-28 with the transition state analogue. This analysis indicates that the activation energy depends on a complex balance of several stereoelectronic effects which are controlled by an extensive network of binding interactions in the active site. Thus in this instance the combinatorial diversity of the immune system provided both an efficient catalyst for a reaction where no enzyme is known, as well as an opportunity to explore the mechanisms and evolution of biological catalysis.
H D Ulrich; E Mundorff; B D Santarsiero; E M Driggers; R C Stevens; P G Schultz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Nature     Volume:  389     ISSN:  0028-0836     ISO Abbreviation:  Nature     Publication Date:  1997 Sep 
Date Detail:
Created Date:  1997-09-30     Completed Date:  1997-09-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  271-5     Citation Subset:  IM    
Howard Hughes Medical Institute, University of California, Berkeley 94720, USA.
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MeSH Terms
Aldehydes / metabolism
Alkadienes / metabolism
Amino Acid Sequence
Antibodies, Catalytic / chemistry*,  genetics,  metabolism
Antibodies, Monoclonal / chemistry*,  genetics,  metabolism
Cloning, Molecular
Crystallography, X-Ray
Evolution, Molecular*
Germ-Line Mutation
Immunoglobulin Variable Region / genetics
Molecular Sequence Data
Protein Conformation
Reg. No./Substance:
0/Aldehydes; 0/Alkadienes; 0/Antibodies, Catalytic; 0/Antibodies, Monoclonal; 0/Immunoglobulin Variable Region

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