An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution

Jari Yli-Kauhaluoma, Andreas Heine, Enrico Stura, Changshou Gao, Kim Janda, Ian Wilson, Qiaolin Deng, Brett Beno, Kendall Houk

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Abstract

A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system.
The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess.
The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control.
Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid–H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate.
This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity.
Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exostereoisomer is the preferred product.
Original languageEnglish
Pages (from-to)1934-1940
JournalScience
Volume279
Issue number5358
DOIs
Publication statusPublished - 1998
MoE publication typeA1 Journal article-refereed

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Antibodies
Hydrogen bonds
Catalytic Antibodies
Stereoselectivity
Lewis Acids
Carbamates
Immune system
Asparagine
Catalysis
Tyrosine
Crystal structure
Catalysts
Substrates
Enzymes
Proteins
Experiments

Cite this

Yli-Kauhaluoma, J., Heine, A., Stura, E., Gao, C., Janda, K., Wilson, I., ... Houk, K. (1998). An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution. Science, 279(5358), 1934-1940. https://doi.org/10.1126/science.279.5358.1934
Yli-Kauhaluoma, Jari ; Heine, Andreas ; Stura, Enrico ; Gao, Changshou ; Janda, Kim ; Wilson, Ian ; Deng, Qiaolin ; Beno, Brett ; Houk, Kendall. / An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution. In: Science. 1998 ; Vol. 279, No. 5358. pp. 1934-1940.
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abstract = "A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid–H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exostereoisomer is the preferred product.",
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Yli-Kauhaluoma, J, Heine, A, Stura, E, Gao, C, Janda, K, Wilson, I, Deng, Q, Beno, B & Houk, K 1998, 'An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution', Science, vol. 279, no. 5358, pp. 1934-1940. https://doi.org/10.1126/science.279.5358.1934

An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution. / Yli-Kauhaluoma, Jari; Heine, Andreas; Stura, Enrico; Gao, Changshou; Janda, Kim; Wilson, Ian; Deng, Qiaolin; Beno, Brett; Houk, Kendall.

In: Science, Vol. 279, No. 5358, 1998, p. 1934-1940.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution

AU - Yli-Kauhaluoma, Jari

AU - Heine, Andreas

AU - Stura, Enrico

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AU - Janda, Kim

AU - Wilson, Ian

AU - Deng, Qiaolin

AU - Beno, Brett

AU - Houk, Kendall

PY - 1998

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AB - A highly specific Diels-Alder protein catalyst was made by manipulating the antibody repertoire of the immune system. The catalytic antibody 13G5 catalyzes a disfavored exo Diels-Alder transformation in a reaction for which there is no natural enzyme counterpart and that yields a single regioisomer in high enantiomeric excess. The crystal structure of the antibody Fab in complex with a ferrocenyl inhibitor containing the essential haptenic core that elicited 13G5 was determined at 1.95 angstrom resolution. Three key antibody residues appear to be responsible for the observed catalysis and product control. Tyrosine-L36 acts as a Lewis acid activating the dienophile for nucleophilic attack, and asparagine-L91 and aspartic acid–H50 form hydrogen bonds to the carboxylate side chain that substitutes for the carbamate diene substrate. This hydrogen-bonding scheme leads to rate acceleration and also pronounced stereoselectivity. Docking experiments with the four possible ortho transition states of the reaction explain the specific exo effect and suggest that the (3R,4R)-exostereoisomer is the preferred product.

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Yli-Kauhaluoma J, Heine A, Stura E, Gao C, Janda K, Wilson I et al. An antibody exo diels-alderase inhibitor complex at 1.95 angstrom resolution. Science. 1998;279(5358):1934-1940. https://doi.org/10.1126/science.279.5358.1934