1MD2

CHOLERA TOXIN B-PENTAMER WITH DECAVALENT LIGAND BMSC-0013

Summary for 1MD2

• Entry DOI: 10.2210/pdb1md2/pdb
• Related: 1LLR 3CHB
• Descriptor: CHOLERA TOXIN B SUBUNIT, [5-(3,4,5-TRIHYDROXY-6-HYDROXYMETHYL-TETRAHYDRO-PYRAN-2-YLCARBAMOYL)-PENTYL]-CARBAMIC ACID METHYL ESTER, 3-ETHYLAMINO-4-METHYLAMINO-CYCLOBUTANE-1,2-DIONE, ... (5 entities in total)
• Functional Keywords: multivalent inhibitor toxin, toxin
• Biological source: Vibrio cholerae
• Total number of polymer chains: 5
• Total formula weight: 60366.87

Authors

Zhang, Z.,Merritt, E.A.,Ahn, M.,Roach, C.,Hol, W.G.J.,Fan, E. (deposition date: 2002-08-06, release date: 2002-12-11, Last modification date: 2024-11-06)

Primary citation

Zhang, Z.,Merritt, E.A.,Ahn, M.,Roach, C.,Hou, Z.,Verlinde, C.L.,Hol, W.G.,Fan, E.
Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin.
J.Am.Chem.Soc., 124:12991-12998, 2002

PubMed 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.

PubMed: 12405825
DOI: 10.1021/ja027584k

Experimental method

X-RAY DIFFRACTION (1.45 Å)