Inhibition of sickle β-chain (β(S))-dependent polymerization by nonhuman α-chains

A superinhibitory mouse-horse chimeric α-chain

Parimala Nacharaju, Rajendra Prasad Roy, Steven P. White, Ronald L. Nagel, A. Seetharama Acharya

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Horse α-chain inhibits sickle β-chain-dependent polymerization; however, its inhibitory potential is not as high as that of mouse α-chain. Horse α-(1-30) and α-(31-141) segments make, respectively, minor and major contributions to the inhibitory potential of horse α-chain. The sum of the inhibitory potential of the two segments does not account for the inhibitory potential of the full-length horse α-chain. Although the polymerization inhibitory potential of horse α-chain is lower than mouse α-chain, the inhibitory potential of horse α-(31-141) is comparable to that of mouse α- (31-141). When mouse α-(1-30) is stitched to horse α-(31-141), the product is a chimeric α-chain with an inhibitory potential greater than mouse α- chain. In contrast, the stitching of horse α-(1-30) with mouse α-(31-141) had no additional inhibitory potential. Molecular modeling studies of HbS containing the mouse-horse chimeric α-chain indicate altered side-chain interactions at the α1β1 interface when compared with HbS. In addition, the AB/GH corner perturbations facilitate a different stereochemistry for the interaction of the ε-amino group of Lys-16(α) with the β-carboxyl group of Asp-116(α), resulting in a decrease in the accessibility of the side chain of Lys-16(α) to the solvent. Based on molecular modeling, we speculate that these perturbations by themselves, or in synergy with the altered conformational aspects of the aα1β1 interactions, represent the molecular basis of the superinhibitory potential of the mouse-horse chimeric α- chains.

Original languageEnglish (US)
Pages (from-to)27869-27876
Number of pages8
JournalJournal of Biological Chemistry
Volume272
Issue number44
DOIs
StatePublished - Oct 31 1997

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Molecular modeling
Polymerization
Horses
Stereochemistry

ASJC Scopus subject areas

  • Biochemistry

Cite this

Inhibition of sickle β-chain (β(S))-dependent polymerization by nonhuman α-chains : A superinhibitory mouse-horse chimeric α-chain. / Nacharaju, Parimala; Roy, Rajendra Prasad; White, Steven P.; Nagel, Ronald L.; Acharya, A. Seetharama.

In: Journal of Biological Chemistry, Vol. 272, No. 44, 31.10.1997, p. 27869-27876.

Research output: Contribution to journalArticle

Nacharaju, Parimala ; Roy, Rajendra Prasad ; White, Steven P. ; Nagel, Ronald L. ; Acharya, A. Seetharama. / Inhibition of sickle β-chain (β(S))-dependent polymerization by nonhuman α-chains : A superinhibitory mouse-horse chimeric α-chain. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 44. pp. 27869-27876.
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