PDBsum entry 1md2

Toxin

PDB id: 1md2

Contents

Protein chains

103 a.a.

Ligands

233-233-_SQ ×2

CYN-233

Waters ×674

PDB id:

1md2

Name:

Toxin

Title:

Cholera toxin b-pentamer with decavalent ligand bmsc-0013

Structure:

Cholera toxin b subunit. Chain: d, e, f, g, h. Engineered: yes

Source:

Vibrio cholerae. Organism_taxid: 666. Gene: ctxb. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Pentamer (from PQS)

Resolution:

1.45Å R-factor: 0.125 R-free: 0.164

Authors:

Z.Zhang,E.A.Merritt,M.Ahn,C.Roach,W.G.J.Hol,E.Fan

Key ref:

Z.Zhang et al. (2002). Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin. J Am Chem Soc, 124, 12991-12998. PubMed id: 12405825 DOI: 10.1021/ja027584k

Date:

06-Aug-02 Release date: 11-Dec-02

Protein chains

P01556  (CHTB_VIBCH) -  Cholera enterotoxin subunit B from Vibrio cholerae serotype O1 (strain ATCC 39315 / El Tor Inaba N16961)

Seq: 124 a.a.

Struc: 104 a.a.*

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

DOI no: 10.1021/ja027584k

J Am Chem Soc 124:12991-12998 (2002)

PubMed id: 12405825

Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin.

Z.Zhang, E.A.Merritt, M.Ahn, C.Roach, Z.Hou, C.L.Verlinde, W.G.Hol, E.Fan.

ABSTRACT

The structure-based design of multivalent ligands offers an attractive strategy toward high affinity protein inhibitors. The spatial arrangement of the receptor-binding sites of cholera toxin, the causative agent of the severe diarrheal disease cholera and a member of the AB(5) bacterial toxin family, provides the opportunity of designing branched multivalent ligands with 5-fold symmetry. Our modular synthesis enabled the construction of a family of complex ligands with five flexible arms each ending with a bivalent ligand. The largest of these ligands has a molecular weight of 10.6 kDa. These ligands are capable of simultaneously binding to two toxin B pentamer molecules with high affinity, thus blocking the receptor-binding process of cholera toxin. A more than million-fold improvement over the monovalent ligand in inhibitory power was achieved with the best branched decavalent ligand. This is better than the improvement observed earlier for the corresponding nonbranched pentavalent ligand. Dynamic light scattering studies demonstrate the formation of concentration-dependent unique 1:1 and 1:2 ligand/toxin complexes in solution with no sign of nonspecific aggregation. This is in complete agreement with a crystal structure of the branched multivalent ligand/toxin B pentamer complex solved at 1.45 A resolution that shows the specific 1:2 ligand/toxin complex formation in the solid state. These results reiterate the power of the structure-based design of multivalent protein ligands as a general strategy for achieving high affinity and potent inhibition.