The 10th and 11th residues of short length N-terminal PTH(1-12) analogue are important for its optimum potency.
The 10th and 11th residues of parathyroid hormone PTH(1-12) analogues were substituted to study the structure and function of PTH analogues. The substitution of Ala(10) of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2) with Glu(10) and/or the Arg(11) with Ile(11) markedly decreased cAMP generating activity. Data from circular dichroism (CD) and the nuclear magnetic resonance (NMR) structural analysis of [Ala(3,10,12)(Leu(7)/Phe(7))Arg(11)]rPTH(1-12)NH(2) revealed tight alpha-helical structures, while the Glu(10) and/or Ile(11) substituted analogues showed unstable alpha-helical structures. We conclude that 10th and 11th residues are important for stabilizing its helical conformation and that destabilization of the alpha-helical structure, induced by substituting the above residues, remarkably affect its biological potency.
Lim
S-K
SK
Department of Internal Medicine, School of Medicine, Yonsei University, Seoul, Korea. lsk@yumc.yonsei.ac.kr
Lee
E J
EJ
Kim
H-Y
HY
Lee
W
W
D019943:Amino Acid Substitution; D000818:Animals; D002942:Circular Dichroism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010281:Parathyroid Hormone / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship
D010281:Parathyroid Hormone; D010455:Peptides