1md2
From Proteopedia
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'''CHOLERA TOXIN B-PENTAMER WITH DECAVALENT LIGAND BMSC-0013''' | '''CHOLERA TOXIN B-PENTAMER WITH DECAVALENT LIGAND BMSC-0013''' | ||
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[[Category: Zhang, Z.]] | [[Category: Zhang, Z.]] | ||
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Revision as of 21:53, 2 May 2008
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. 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 Page seeded by OCA on Sat May 3 00:53:59 2008
