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Titolo:
THE ALLOSTERIC TRANSITION OF THE INSULIN HEXAMER IS MODULATED BY HOMOTROPIC AND HETEROTROPIC INTERACTIONS
Autore:
CHOI WE; BRADER ML; AGUILAR V; KAARSHOLM NC; DUNN MF;
Indirizzi:
UNIV CALIF RIVERSIDE,DEPT BIOCHEM 015 RIVERSIDE CA 92521 UNIV CALIF RIVERSIDE,DEPT BIOCHEM 015 RIVERSIDE CA 92521 NOVO RES INST DK-2880 BAGSVAERD DENMARK
Titolo Testata:
Biochemistry
fascicolo: 43, volume: 32, anno: 1993,
pagine: 11638 - 11645
SICI:
0006-2960(1993)32:43<11638:TATOTI>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
ZINC-BINDING DOMAINS; LIGAND-BINDING; PHENOL; SITE; COOPERATIVITY; INTERMEDIATE; HEMOGLOBIN; STABILIZES; PROINSULIN; MECHANISMS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
44
Recensione:
Indirizzi per estratti:
Citazione:
W.E. Choi et al., "THE ALLOSTERIC TRANSITION OF THE INSULIN HEXAMER IS MODULATED BY HOMOTROPIC AND HETEROTROPIC INTERACTIONS", Biochemistry, 32(43), 1993, pp. 11638-11645

Abstract

The allosteric behavior of the Co(II)-substituted insulin hexamer hasbeen investigated using electronic spectroscopy to study the binding of different phenolic analogues and singly charged anions to effector sites on the protein. This work presents the first detailed, quantitative analysis of the ligand-induced T- to R-state allosteric transitionof the insulin hexamer. Recent studies have established that there are two ligand binding processes which stabilize the R-state conformation of the Co(II)-substituted hexamer: the binding of cyclic organic molecules to the six protein pockets present in the Zn(II)-R6 insulin hexamer [Derewenda, U., Derewenda, Z., Dodson, E. J., Dodson, G. G., Reynolds, C. D., Smith, G. D., Sparks, C., & Swensen, D. (1989) Nature 338, 594-596] and the coordination of singly charged anions to the His(B10) metal sites [Brader, M. L., Kaarsholm, N. C., Lee, W. K., & Dunn, M. F. (1991) Biochemistry 30, 6636-6645]. The R6 insulin hexamer is stabilized by heterotropic interactions between the hydrophobic protein pockets and the coordination sites of the His(B10)-bound metal ions. The binding studies with 4-hydroxybenzamide, m-cresol, resorcinol, and phenol presented herein show that, in the absence of inorganic anions, the 4-hydroxybenzamide-induced transition, with a Hill number of 2.8, is the most cooperative, followed by m-cresol, phenol, and resorcinol with Hill numbers of 1.8, 1.4, and 1.2, respectively. The relative effectiveness of these ligands in shifting the allosteric equilibrium in favor of the Co(II)-R6 hexamer was found to be resorcinol > phenol > 4-hydroxybenzamide > m-cresol. In the presence of inorganic anions, thebinding isotherms become less sigmoidal, the Hill numbers approach 1,and the apparent affinities increase. Hence, these monodentate anionsbehave as positive allosteric effectors by coordinating to the His(B10)-bound Co(II) ions. The Co(II)-substituted insulin hexamer is further stabilized by divalent metals such as Ca2+ and Cd2+, which are knownto bind to the Glu(B13) cage located in the center of the insulin hexamer [Hill, C. P., Dauter, Z., Dodson, E. J., Dodson, G. G., & Dunn, M. F. (1991) Biochemistry 30, 917-924]. Therefore, the R-state insulin hexamer is stabilized by a variety of heterotropic and homotropic interactions involving the coordination of singly charged anions to the His(B10)-bound metal ions, hydrogen bonding, and van der Waals interactions between the cyclic organic molecules and the protein pockets.

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Documento generato il 01/10/20 alle ore 01:26:36