1A3L

CATALYSIS OF A DISFAVORED REACTION: AN ANTIBODY EXO DIELS-ALDERASE-TSA-INHIBITOR COMPLEX AT 1.95 A RESOLUTION

Summary for 1A3L

• Entry DOI: 10.2210/pdb1a3l/pdb
• Descriptor: IMMUNOGLOBULIN FAB 13G5 (LIGHT CHAIN), IMMUNOGLOBULIN FAB 13G5 (HEAVY CHAIN), 1-CARBOXY-1'-[(DIMETHYLAMINO)-CARBONYL]FERROCENE, ... (4 entities in total)
• Functional Keywords: diels-alder, disfavored reaction, catalytic antibody, immunoglobulin
• Biological source: Mus musculus (house mouse); More
• Total number of polymer chains: 2
• Total formula weight: 47308.37

Authors

Heine, A.,Wilson, I.A. (deposition date: 1998-01-22, release date: 1999-02-16, Last modification date: 2024-10-30)

Primary citation

Heine, A.,Stura, E.A.,Yli-Kauhaluoma, J.T.,Gao, C.,Deng, Q.,Beno, B.R.,Houk, K.N.,Janda, K.D.,Wilson, I.A.
An antibody exo Diels-Alderase inhibitor complex at 1.95 angstrom resolution.
Science, 279:1934-1940, 1998

PubMed 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)-exo stereoisomer is the preferred product.

PubMed: 9506943
DOI: 10.1126/science.279.5358.1934

Experimental method

X-RAY DIFFRACTION (1.95 Å)