1md2

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spinqualitylabelsall models 1md2, resolution 1.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CHOLERA TOXIN B-PENTAMER WITH DECAVALENT LIGAND BMSC-0013

Overview

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.

About this Structure

1MD2 is a Single protein structure of sequence from Vibrio cholerae with CYN, S, 233 and SQ as ligands. Full crystallographic information is available from OCA.

Reference

Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin., Zhang Z, Merritt EA, Ahn M, Roach C, Hou Z, Verlinde CL, Hol WG, Fan E, J Am Chem Soc. 2002 Nov 6;124(44):12991-8. PMID:12405825

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