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

Debler EW, Müller R, Hilvert D, Wilson IA
Proc Natl Acad Sci U S A 106 18539-44 (2009)
Related entries: 3fo1, 3fo2

Cited: 18 times
EuropePMC logo PMID: 19846764

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.

Articles - 3fo0 mentioned but not cited (4)

  1. AbDesign: An algorithm for combinatorial backbone design guided by natural conformations and sequences. Lapidoth GD, Baran D, Pszolla GM, Norn C, Alon A, Tyka MD, Fleishman SJ. Proteins 83 1385-1406 (2015)
  2. An anti-hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop. Fanning SW, Horn JR. Protein Sci 20 1196-1207 (2011)
  3. Challenges and advances in validating enzyme design proposals: the case of kemp eliminase catalysis. Frushicheva MP, Cao J, Warshel A. Biochemistry 50 3849-3858 (2011)
  4. An aspartate and a water molecule mediate efficient acid-base catalysis in a tailored antibody pocket. Debler EW, Müller R, Hilvert D, Wilson IA. Proc Natl Acad Sci U S A 106 18539-18544 (2009)


Reviews citing this publication (5)

  1. Computational enzyme design. Kiss G, Çelebi-Ölçüm N, Moretti R, Baker D, Houk KN. Angew Chem Int Ed Engl 52 5700-5725 (2013)
  2. Design of protein catalysts. Hilvert D. Annu Rev Biochem 82 447-470 (2013)
  3. Catalytic efficiency of designed catalytic proteins. Korendovych IV, DeGrado WF. Curr Opin Struct Biol 27 113-121 (2014)
  4. Computational strategies for the design of new enzymatic functions. Świderek K, Tuñón I, Moliner V, Bertran J. Arch Biochem Biophys 582 68-79 (2015)
  5. Synthetic, Switchable Enzymes. Norris V, Krylov SN, Agarwal PK, White GJ. J Mol Microbiol Biotechnol 27 117-127 (2017)

Articles citing this publication (9)

  1. Bridging the gaps in design methodologies by evolutionary optimization of the stability and proficiency of designed Kemp eliminase KE59. Khersonsky O, Kiss G, Röthlisberger D, Dym O, Albeck S, Houk KN, Baker D, Tawfik DS. Proc Natl Acad Sci U S A 109 10358-10363 (2012)
  2. Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis. Richard JP. J Am Chem Soc 141 3320-3331 (2019)
  3. Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase. Frushicheva MP, Cao J, Chu ZT, Warshel A. Proc Natl Acad Sci U S A 107 16869-16874 (2010)
  4. Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions. Brylinski M. Chem Biol Drug Des 91 380-390 (2018)
  5. A single mutation in a regulatory protein produces evolvable allosterically regulated catalyst of nonnatural reaction. Moroz OV, Moroz YS, Wu Y, Olsen AB, Cheng H, Mack KL, McLaughlin JM, Raymond EA, Zhezherya K, Roder H, Korendovych IV. Angew Chem Int Ed Engl 52 6246-6249 (2013)
  6. A novel molecular analysis of genes encoding catalytic antibodies. Le Minoux D, Mahendra A, Kaveri S, Limnios N, Friboulet A, Avalle B, Boquet D, Lacroix-Desmazes S, Padiolleau-Lefèvre S. Mol Immunol 50 160-168 (2012)
  7. NMR-guided directed evolution. Bhattacharya S, Margheritis EG, Takahashi K, Kulesha A, D'Souza A, Kim I, Yoon JH, Tame JRH, Volkov AN, Makhlynets OV, Korendovych IV. Nature 610 389-393 (2022)
  8. BIOPHYSICS. Response to Comments on "Extreme electric fields power catalysis in the active site of ketosteroid isomerase". Fried SD, Boxer SG. Science 349 936 (2015)
  9. Conserved water molecules in bacterial serine hydroxymethyltransferases. Milano T, Di Salvo ML, Angelaccio S, Pascarella S. Protein Eng Des Sel 28 415-426 (2015)


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