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Type I beta-turn conformation is important for biological activity of the melanocyte-stimulating hormone analogues

 Song‐Zhe Li  ;  Jung‐Hoon Lee  ;  Weontae Lee  ;  Chang‐Ju Yoon  ;  Ja‐Hyun Baik  ;  Sung‐Kil Lim 
 European Journal of Biochemistry, Vol.265(1) : 430-440, 1999 
Journal Title
Issue Date
Animals ; Binding, Competitive ; CHO Cells ; Cricetinae ; Cyclic AMP/metabolism ; Dose-Response Relationship, Drug ; Humans ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Structure, Secondary ; Rats ; Receptor, Melanocortin, Type 3 ; Receptor, Melanocortin, Type 4 ; Receptors, Corticotropin/genetics ; Receptors, Corticotropin/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism* ; Signal Transduction ; Structure-Activity Relationship ; alpha-MSH/analogs & derivatives* ; alpha-MSH/pharmacology*
In order to define which structure of alpha-melanocyte-stimulating hormone (MSH) analogues plays a critical role for ligand-receptor interaction and selectivity, we analysed receptor-binding and cAMP-generating activity in Chinese hamster ovary cell lines stably transfected with rMC3R and hMC4R, as well as the NMR structures of chemically synthesized alpha-MSH analogues. Compared with [Ahx4]alpha-MSH, the linear MTII designated as alpha-MSH-ND revealed a preference for the MC4R, whereas its IC50 and EC50 values were comparable to those of MTII reported previously. Truncation of Ahx4 and Asp5 of alpha-MSH-ND remarkably decreased the receptor-binding and cAMP-generating activity. Meanwhile, maximum cAMP-generating activity was observed at a higher concentration (10(-5) M) of alpha-MSH-ND(6-10), and MC4R preference was changed into MC3R preference. In contrast, [Gln6]alpha-MSH-ND(6-10) lost its cAMP-generating activity almost completely, even though it bound to both receptors. Whereas the solution conformation of alpha-MSH-ND revealed a stable type I beta-turn structure, [Gln6]alpha-MSH-ND(6-10) revealed a tight gamma-turn composed of Gln6-D-Phe7-Arg8. Replacement of the His6 residue of alpha-MSH-ND by Gln, Asn, Arg or Lys decreased not only the receptor binding, but also the cAMP-generating activity in both the MC3R and the MC4R. The structure of [Gln6]alpha-MSH-ND exhibited a stable type I' beta-turn comprising Asp5, Gln6, D-Phe7 and Arg8. [Lys6]alpha-MSH-ND showed a greatly reduced binding affinity and cAMP-generating activity with the loss of MC4R selectivity. In NMR studies, [Lys6]alpha-MSH-ND also demonstrated a gamma-turn conformation around Lys6-DPhe7-Arg8. From the above results, we conclude that a type I beta-turn conformation comprising the residues Asp5-His6-(D-Phe7)-Arg8 was important for receptor binding and activation, as well as the selectivity of MSH analogues.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lim, Sung Kil(임승길)
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