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Non-standard insulin design: structure-activity relationships at the periphery of the insulin receptor.

Weiss MA, Wan Z, Zhao M, Chu YC, Nakagawa SH, Burke GT, Jia W, Hellmich R, Katsoyannis PG
J Mol Biol 315 103-11 (2002)
Related entries: 1iog, 1ioh, 1jca, 1vkt, 2jmn

Cited: 12 times
EuropePMC logo PMID: 11779231

Abstract

The design of insulin analogues has emphasized stabilization or destabilization of structural elements according to established principles of protein folding. To this end, solvent-exposed side-chains extrinsic to the receptor-binding surface provide convenient sites of modification. An example is provided by an unfavorable helical C-cap (Thr(A8)) whose substitution by favorable amino acids (His(A8) or Arg(A8)) has yielded analogues of improved stability. Remarkably, these analogues also exhibit enhanced activity, suggesting that activity may correlate with stability. Here, we test this hypothesis by substitution of diaminobutyric acid (Dab(A8)), like threonine an amino acid of low helical propensity. The crystal structure of Dab(A8)-insulin is similar to those of native insulin and the related analogue Lys(A8)-insulin. Although no more stable than native insulin, the non-standard analogue is twice as active. Stability and affinity can therefore be uncoupled. To investigate alternative mechanisms by which A8 substitutions enhance activity, multiple substitutions were introduced. Surprisingly, diverse aliphatic, aromatic and polar side-chains enhance receptor binding and biological activity. Because no relationship is observed between activity and helical propensity, we propose that local interactions between the A8 side-chain and an edge of the hormone-receptor interface modulate affinity. Dab(A8)-insulin illustrates the utility of non-standard amino acids in hypothesis-driven protein design.

Reviews citing this publication (2)

  1. A Review of the Biosynthesis and Structural Implications of Insulin Gene Mutations Linked to Human Disease. Ataie-Ashtiani S, Forbes B. Cells 12 1008 (2023)
  2. Diabetes-Associated Mutations in Proinsulin Provide a "Molecular Rheostat" of Nascent Foldability. Dhayalan B, Weiss MA. Curr Diab Rep 22 85-94 (2022)

Articles citing this publication (10)

  1. How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor. Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA. J Mol Biol 341 529-550 (2004)
  2. Chiral mutagenesis of insulin. Foldability and function are inversely regulated by a stereospecific switch in the B chain. Nakagawa SH, Zhao M, Hua QX, Hu SQ, Wan ZL, Jia W, Weiss MA. Biochemistry 44 4984-4999 (2005)
  3. An Achilles' heel in an amyloidogenic protein and its repair: insulin fibrillation and therapeutic design. Yang Y, Petkova A, Huang K, Xu B, Hua QX, Ye IJ, Chu YC, Hu SQ, Phillips NB, Whittaker J, Ismail-Beigi F, Mackin RB, Katsoyannis PG, Tycko R, Weiss MA. J Biol Chem 285 10806-10821 (2010)
  4. Behavior in the eukaryotic secretory pathway of insulin-containing fusion proteins and single-chain insulins bearing various B-chain mutations. Zhang BY, Liu M, Arvan P. J Biol Chem 278 3687-3693 (2003)
  5. A new cell secreting insulin. Roy SS, Mukherjee M, Bhattacharya S, Mandal CN, Kumar LR, Dasgupta S, Bandyopadhyay I, Wakabayashi K. Endocrinology 144 1585-1593 (2003)
  6. Rational design of affinity peptide ligand by flexible docking simulation. Liu FF, Wang T, Dong XY, Sun Y. J Chromatogr A 1146 41-50 (2007)
  7. Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications. Zhao M, Wan ZL, Whittaker L, Xu B, Phillips NB, Katsoyannis PG, Ismail-Beigi F, Whittaker J, Weiss MA. J Biol Chem 284 32178-32187 (2009)
  8. Evolution of preproinsulin gene in birds. Simon J, Laurent S, Grolleau G, Thoraval P, Soubieux D, Rasschaert D. Mol Phylogenet Evol 30 755-766 (2004)
  9. Human insulin A-chain peptide analog(s) with in vitro biological activity. Le Flem G, Pecher J, Le Flem-Bonhomme V, Withdrawn A, Rochette J, Pujol JP, Bogdanowicz P. Cell Biochem Funct 27 370-377 (2009)
  10. Novel Pathogenic De Novo INS p.T97P Variant Presenting With Severe Neonatal DKA. Lal RA, Moeller HP, Thomson EA, Horton TM, Lee S, Freeman R, Prahalad P, Poon ASY, Annes JP. Endocrinology 163 bqab246 (2022)


Related citations provided by authors (4)

  1. Diabetes-associated mutations in a beta-cell transcription factor destabilize an antiparallel "mini-zipper" in a dimerization interface.. Hua QX, Zhao M, Narayana N, Nakagawa SH, Jia W, Weiss MA Proc Natl Acad Sci U S A 97 1999-2004 (2000)
  2. The relationship between insulin bioactivity and structure in the NH2-terminal A-chain helix.. Olsen HB, Ludvigsen S, Kaarsholm NC J Mol Biol 284 477-88 (1998)
  3. Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.. Hua QX, Hu SQ, Frank BH, Jia W, Chu YC, Wang SH, Burke GT, Katsoyannis PG, Weiss MA J Mol Biol 264 390-403 (1996)
  4. A Proposed Interaction Model of the Insulin Molecule with its Receptor. Liang DC, Chang WR, Wan ZL, Vijayan NM Biophys. Chem. 50 63-71 (1994)

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