1ND0

CATIONIC CYCLIZATION ANTIBODY 4C6 COMPLEX WITH TRANSITION STATE ANALOG

Summary for 1ND0

• Entry DOI: 10.2210/pdb1nd0/pdb
• Related: 1NCW
• Descriptor: IMMUNOGLOBULIN IGG2A, (1s,4s)-4-[dimethyl(phenyl)silyl]-1-methylpiperidine 1-oxide, SULFATE ION, ... (5 entities in total)
• Functional Keywords: immunoglobulin, catalytic antibody, cationic cyclization reaction, immune system
• Biological source: Mus musculus (house mouse); More
• Cellular location: Cell membrane; Single-pass membrane protein (Potential): P01865
• Total number of polymer chains: 8
• Total formula weight: 193524.35

Authors

Zhu, X.,Wilson, I.A. (deposition date: 2002-12-05, release date: 2003-05-13, Last modification date: 2023-08-16)

Primary citation

Zhu, X.,Heine, A.,Monnat, F.,Houk, K.N.,Janda, K.D.,Wilson, I.A.
Structural Basis for Antibody Catalysis of a Cationic Cyclization Reaction
J.Mol.Biol., 329:69-83, 2003

PubMed Abstract: Antibody 4C6 efficiently catalyzes a cationic cyclization reaction. Crystal structures of the antibody 4C6 Fab in complex with benzoic acid and in complex with its eliciting hapten were determined to 1.30A and 2.45A resolution, respectively. These crystal structures, together with computational analysis, have elucidated a possible mechanism for the monocyclization reaction. The hapten complex revealed a combining site pocket with high shape complementarity to the hapten. This active site cleft is dominated by aromatic residues that shield the highly reactive carbocation intermediates from solvent and stabilize the carbocation intermediates through cation-pi interactions. Modeling of an acyclic olefinic sulfonate ester substrate and the transition state (TS) structures shows that the chair-like transition state is favored, and trapping by water directly produces trans-2-(dimethylphenylsilyl)-cyclohexanol, whereas the less favored boat-like transition state leads to cyclohexene. The only significant change observed upon hapten binding is a side-chain rotation of Trp(L89), which reorients to form the base of the combining site. Intriguingly, a benzoic acid molecule was sequestered in the combining site of the unliganded antibody. The 4C6 active site was compared to that observed in a previously reported tandem cyclization antibody 19A4 hapten complex. These cationic cyclization antibodies exhibit convergent structural features with terpenoid cyclases that appear to be important for catalysis.

PubMed: 12742019
DOI: 10.1016/S0022-2836(03)00406-6

Experimental method

X-RAY DIFFRACTION (2.45 Å)