CRYSTAL-STRUCTURE OF THE COMPLEX OF A CATALYTIC ANTIBODY FAB FRAGMENTWITH A TRANSITION-STATE ANALOG - STRUCTURAL SIMILARITIES IN ESTERASE-LIKE CATALYTIC ANTIBODIES

The x-ray structure of the complex of a catalytic antibody Fab fragmen t with a phosphonate transition-state analog has been determined. The antibody (CNJ206) catalyzes the hydrolysis of p-nitrophenyl esters wit h significant rate enhancement and substrate specificity. Comparison o f this structure with that of the uncomplexed Fab fragment suggests ha pten-induced conformational changes: the shape of the combining site c hanges from a shallow groove in the uncomplexed Fab to a deep pocket w here the hapten is buried. Three hydrogen-bond donors appear to stabil ize the charged phosphonate group of the hapten: two NH groups of the heavy (H) chain complementarity-determining region 3 (H3 CDR) polypept ide chain and the side-chain of histidine-H35 in the H chain (His-H35) in the H1 CDR. The combining site shows striking structural similarit ies to that of antibody 17E8, which also has esterase activity. Both c atalytic antibody (''abzyme'') structures suggest that oxyanion stabil ization plays a significant role in their rate acceleration. Additiona l catalytic groups that improve efficiency are not necessarily induced by the eliciting hapten; these groups may occur because of the variab ility in the combining sites of different monoclonal antibodies that b ind to the same hapten.