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R6 hexameric insulin complexed with m-cresol or resorcinol.

G D Smith1, E Ciszak, L A Magrum

  • 1Hauptman-Woodward Medical Research Institute, 73 High Street, Buffalo, NY 14203, USA. smith@hwi.buffalo.edu

Acta Crystallographica. Section D, Biological Crystallography
|November 28, 2000
PubMed
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Researchers determined the structures of three R(6) human insulin hexamers using X-ray crystallography. Phenolic derivatives bind to specific sites, influencing insulin

Area of Science:

  • Biochemistry
  • Structural Biology
  • Crystallography

Background:

  • Human insulin exists in hexameric forms, crucial for storage and release.
  • Understanding insulin structure is key to developing improved therapeutic formulations.

Purpose of the Study:

  • To elucidate the structural basis of R(6) human insulin hexamers.
  • To identify binding sites for phenolic derivatives and their interactions.
  • To investigate the conformational changes associated with insulin's T to R transition.

Main Methods:

  • X-ray crystallography was employed to determine the structures of three R(6) human insulin hexamer crystal forms.
  • High-resolution diffraction data (1.78-1.9 Å) were collected and structures were refined.
  • Analysis of atomic interactions and conformational differences between hexamer states.

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Main Results:

  • Three R(6) human insulin hexamer structures (monoclinic and rhombohedral) were determined at high resolution.
  • Phenolic derivatives were consistently found bound at a specific phenolic site, forming hydrogen bonds with CysA6 and CysA11.
  • Additional binding sites for phenolic derivatives were identified within or between hexamers.
  • Minor structural variations were observed, including sodium ion coordination affecting B chain N-termini and packing differences.
  • Conformational changes in GluB13 side chains correlated with the T to R conformational transition.

Conclusions:

  • The R(6) human insulin hexamer structure is well-defined, with phenolic derivatives occupying specific binding pockets.
  • Phenolic binding appears to stabilize the R(6) state.
  • The deprotonation of GluB13 side chains is linked to the T to R conformational transition, providing insights into insulin's allosteric regulation.