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Carboxylate Ions Are Strong Allosteric Ligands for the HisB10 Sites of the R-State Insulin Hexamer

Huang, Sheng Tung and Choi, Wonjae E. and Bloom, Curtis and Leuenberger, Melissa and Dunn, Michael F. (1997) Carboxylate Ions Are Strong Allosteric Ligands for the HisB10 Sites of the R-State Insulin Hexamer. Biochemistry, 36 (32). pp. 9878-9888. ISSN 0006-2960. doi:10.1021/bi9701639.

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The insulin hexamer is an allosteric protein which displays positive and negative cooperativity and half-site reactivity that is modulated by strong homotropic and heterotropic ligand binding interactions at two different loci. These loci consist of phenolic pockets situated on the dimer−dimer interfaces of T−R and R−R subunit pairs and of anion sites comprising the HisB10 metal ion sites of the R_3 units of the T_3R_3 and R_6 states. In this study, we show that suitably tailored organic carboxylates are strong allosteric effectors with relatively high affinities for the R-state HisB10 metal sites. Methods of quantifying the relative affinities of ligands for these sites in both Co(II)- and Zn(II)-substituted insulin hexamers are presented. These analyses show that, in addition to the electron density on the ion, the carboxylate affinity is influenced by polar, nonpolar, and hydrophobic interactions between substituents on the carboxylate and the amphipathic protein surface of the narrow tunnel which controls ligand access to the metal ion. Since the binding of anions to the HisB10 site makes a critically important contribution to the stability of the T_3R_3 and R_6 forms of the insulin hexamer, the design of high-affinity ligands with a carboxylate donor for coordination to the metal ion provides an opportunity for constructing insulin formulations with improved pharmaceutical properties.

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Additional Information:© 1997 American Chemical Society. Received 24 January 1997. Published online 12 August 1997. We are indebted to G. David Smith for providing the coordinates of the Zn(II)-R6 chloride complex we used in modeling the binding of carboxylates to the HisB10 sites. Abstract published in Advance ACS Abstracts, August 1, 1997.
Issue or Number:32
Record Number:CaltechAUTHORS:20180213-090536875
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Official Citation:Carboxylate Ions Are Strong Allosteric Ligands for the HisB10 Sites of the R-State Insulin Hexamer Sheng Tung Huang, Wonjae E. Choi, Curtis Bloom, Melissa Leuenberger, and Michael F. Dunn Biochemistry 1997 36 (32), 9878-9888 DOI: 10.1021/bi9701639
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84806
Deposited By: Ruth Sustaita
Deposited On:13 Feb 2018 19:39
Last Modified:15 Nov 2021 20:23

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