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An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket

Academic Article
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Overview

related to degree

  • Debler, Erik Werner, Ph.D. in Biology, Scripps Research 2002 - 2006

authors

  • Debler, Erik Werner
  • Muller, R.
  • Hilvert, Donald M.
  • Wilson, Ian

publication date

  • November 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Design of catalysts featuring multiple functional groups is a desirable, yet formidable goal. Antibody 13G5, which accelerates the cleavage of unactivated benzisoxazoles, is one of few artificial enzymes that harness an acid and a base to achieve efficient proton transfer. X-ray structures of the Fab-hapten complexes of wild-type 13G5 and active-site variants now afford detailed insights into its mechanism. The parent antibody preorganizes Asp(H35) and Glu(L34) to abstract a proton from substrate and to orient a water molecule for leaving group stabilization, respectively. Remodeling the environment of the hydrogen bond donor with a compensatory network of ordered waters, as seen in the Glu(L34) to alanine mutant, leads to an impressive 10(9)-fold rate acceleration over the nonenzymatic reaction with acetate, illustrating the utility of buried water molecules in bifunctional catalysis. Generalization of these design principles may aid in creation of catalysts for other important chemical transformations.

subject areas

  • Acids
  • Alkalies
  • Antibodies
  • Aspartic Acid
  • Catalysis
  • Crystallography, X-Ray
  • Haptens
  • Hydrogen-Ion Concentration
  • Immunoglobulin Fab Fragments
  • Ligands
  • Models, Molecular
  • Mutant Proteins
  • Protein Stability
  • Protons
  • Static Electricity
  • Structure-Activity Relationship
  • Water
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Research

keywords

  • catalytic antibody
  • crystal structure
  • enzyme design
  • enzyme mechanism
  • proton transfer
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Identity

PubMed Central ID

  • PMC2774029

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0902700106

PubMed ID

  • 19846764
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Additional Document Info

start page

  • 18539

end page

  • 18544

volume

  • 106

issue

  • 44

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