PDBsum entry 1jgv

Immune system

PDB id: 1jgv

Contents

Protein chains

220 a.a. *

218 a.a. *

Waters ×246

* Residue conservation analysis

PDB id:

1jgv

Name:

Immune system

Title:

Structural basis for disfavored elimination reaction in catalytic antibody 1d4

Structure:

Antibody light chain. Chain: l. Antibody heavy chain. Chain: h

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Strain: balbc. Other_details: purified from igg derived from ascites fluid. Other_details: purified from igg derived from ascites fluid

Biol. unit:

Dimer (from PQS)

Resolution:

1.85Å R-factor: 0.206 R-free: 0.247

Authors:

N.A.Larsen,A.Heine,L.Crane,B.F.Cravatt,R.A.Lerner,I.A.Wilson

Key ref:

N.A.Larsen et al. (2001). Structural basis for a disfavored elimination reaction in catalytic antibody 1D4. J Mol Biol, 314, 93. PubMed id: 11724535 DOI: 10.1006/jmbi.2001.5112

Date:

26-Jun-01 Release date: 05-Dec-01

Protein chain

Q52L64  (Q52L64_MOUSE) -  ENSMUSG00000076577 protein from Mus musculus

Seq: 240 a.a.

Struc: 220 a.a.*

Protein chain

Q91Z05  (Q91Z05_MOUSE) -  Ighg protein from Mus musculus

Seq: 473 a.a.

Struc: 218 a.a.*

* PDB and UniProt seqs differ at 91 residue positions (black crosses)

DOI no: 10.1006/jmbi.2001.5112

J Mol Biol 314:93 (2001)

PubMed id: 11724535

Structural basis for a disfavored elimination reaction in catalytic antibody 1D4.

N.A.Larsen, A.Heine, L.Crane, B.F.Cravatt, R.A.Lerner, I.A.Wilson.

ABSTRACT

Murine antibody 1D4 selectively catalyzes a highly disfavored beta-elimination reaction. Crystal structures of unliganded 1D4 and 1D4 in complex with a transition-state analog (TSA) have elucidated a possible general base mode of catalysis. The structures of the unliganded and liganded Fabs were determined to 1.80 and 1.85 A resolution, respectively. The structure of the complex reveals a binding pocket with high shape complementarity to the TSA, which is recruited to coerce the substrate into the sterically demanding, eclipsed conformation that is required for catalysis. A histidine residue and two water molecules are likely involved in the catalysis. The structure supports either a concerted E2 or stepwise E1cB-like mechanism for elimination. Finally, the liganded 1D4 structure shows minor conformational rearrangements in CDR H2, indicative of induced-fit binding of the hapten. 1D4 has pushed the boundaries of antibody-mediated catalysis into the realm of disfavored reactions and, hence, represents an important milestone in the development of this technology.

Selected figure(s)

Figure 3.
Figure 3. Stereo representations of the hapten interactions in the antigen-binding pocket. (a) Hydrogen bonds are shown as broken green lines. Arg^H100 forms an apparent cation-π sandwich with Tyr^L32 and the phenyl ring in the hapten[21], and prevents further interactions of the hapten with CDR L1 or L2. (b) The side view of the binding pocket shows that the majority of the side-chain interactions are derived from the heavy chain. His^H58 stacks against the second phenyl ring in the substrate. Leu^L96 has been omitted from this view for clarity.

Figure 6.
Figure 6. Substrate modeling by superposition on the hapten. Most of the antibody interactions with the hapten and substrate alike are directed towards the two phenyl rings. The putative hydroxide ion is positioned to abstract the hydrogen atom from the substrate, while the water molecule forms a hydrogen bond with the substrate carbonyl group, possibly lowering the p K[a] of the abstracted proton.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 314, 93-0) copyright 2001.

Figures were selected by an automated process.