PDBsum entry 25c8

Catalytic antibody

PDB id: 25c8

Contents

Protein chains

212 a.a. *

217 a.a. *

Ligands

GEP

Waters ×232

* Residue conservation analysis

PDB id:

25c8

Name:

Catalytic antibody

Title:

Catalytic antibody 5c8, fab-hapten complex

Structure:

Igg 5c8. Chain: l. Fragment: fab. Igg 5c8. Chain: h. Fragment: fab

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Organism_taxid: 10090

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å R-factor: 0.229 R-free: 0.292

Authors:

K.Gruber,I.A.Wilson

Key ref:

K.Gruber et al. (1999). Structural basis for antibody catalysis of a disfavored ring closure reaction. Biochemistry, 38, 7062-7074. PubMed id: 10353817 DOI: 10.1021/bi990210s

Date:

18-Mar-98 Release date: 23-Mar-99

Protein chain

P01837  (IGKC_MOUSE) -  Immunoglobulin kappa constant from Mus musculus

Seq: 107 a.a.

Struc: 212 a.a.

Protein chain

P01869  (IGH1M_MOUSE) -  Ig gamma-1 chain C region, membrane-bound form from Mus musculus

Seq: 393 a.a.

Struc: 217 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1021/bi990210s

Biochemistry 38:7062-7074 (1999)

PubMed id: 10353817

Structural basis for antibody catalysis of a disfavored ring closure reaction.

K.Gruber, B.Zhou, K.N.Houk, R.A.Lerner, C.G.Shevlin, I.A.Wilson.

ABSTRACT

The catalysis of disfavored chemical reactions, especially those with no known natural enzyme counterparts, is one of the most promising achievements of catalytic antibody research. Antibodies 5C8, 14B9, 17F6, and 26D9, elicited by two different transition-state analogues, catalyze disfavored endo-tet cyclization reactions of trans-epoxy alcohols, in formal violation of Baldwin's rules for ring closure. Thus far, neither chemical nor enzyme catalysis has been capable of emulating the extraordinary activity and specificity of these antibodies. X-ray structures of two complexes of Fab 5C8 with the original hapten and with an inhibitor have been determined to 2.0 A resolution. The Fab structure has an active site that contains a putative catalytic diad, consisting of AspH95 and HisL89, capable of general acid/base catalysis. The stabilization of a positive charge that develops along the reaction coordinate appears to be an important factor for rate enhancement and for directing the reaction along the otherwise disfavored pathway. Sequence analysis of the four catalytic antibodies, as well as four inactive antibodies that strongly bind the transition-state analogues, suggests a conserved catalytic mechanism. The occurrence of the putative base HisL89 in all active antibodies, its absence in three out of the four analyzed inactive antibodies, and the rarity of a histidine at this position in immunoglobulins support an important catalytic role for this residue.