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PDBsum entry 1md2
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-Binding of cholera toxin.
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Authors
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Z.Zhang,
E.A.Merritt,
M.Ahn,
C.Roach,
Z.Hou,
C.L.Verlinde,
W.G.Hol,
E.Fan.
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Ref.
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J Am Chem Soc, 2002,
124,
12991-12998.
[DOI no: ]
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PubMed id
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Abstract
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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.
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