1BH0

STRUCTURE OF A GLUCAGON ANALOG

1BH0 の概要

• エントリーDOI: 10.2210/pdb1bh0/pdb
• 分子名称: GLUCAGON (1 entity in total)
• 機能のキーワード: synthetic hormone
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 3444.78

構造登録者

Sturm, N.S.,Lin, Y.,Burley, S.K.,Krstenansky, J.L.,Ahn, J.-M.,Azizeh, B.Y.,Trivedi, D.,Hruby, V.J. (登録日: 1998-06-11, 公開日: 1998-11-04, 最終更新日: 2024-02-07)

主引用文献

Sturm, N.S.,Lin, Y.,Burley, S.K.,Krstenansky, J.L.,Ahn, J.M.,Azizeh, B.Y.,Trivedi, D.,Hruby, V.J.
Structure-function studies on positions 17, 18, and 21 replacement analogues of glucagon: the importance of charged residues and salt bridges in glucagon biological activity.
J.Med.Chem., 41:2693-2700, 1998

PubMed Abstract: We have designed and synthesized eight compounds 2-9 which incorporate various amino acid residues in positions 17, 18, and 21 of the glucagon molecule: 2, [Lys17]glucagon amide; 3, [Lys18]glucagon amide; 4, [Nle17,Lys18,Glu21]glucagon amide; 5, [Orn17,18, Glu21]glucagon amide; 6, [d-Arg17]glucagon; 7, [d-Arg18]glucagon; 8, [d-Phe17]glucagon; and 9, [d-Phe18]glucagon. Compared to glucagon (IC50 = 1.5 nM), analogues 2-9 were found to have binding affinity IC50 values (in nM) of 0.7, 4.1, 1.0, 2.0, 5.0, 25.0, 43.0, and 32.0, respectively. When these compounds were tested for their ability to stimulate adenylate cyclase (AC) activity, they were found to be full or partial agonists having maximum stimulation values of 100, 100, 100, 100, 87, 78, 94, and 100%, respectively. On the basis of the X-ray crystal structure of [Lys17,18,Glu21]glucagon amide reported here, the ability to form a salt bridge between Lys18 and Glu21 is probably key to their increased binding and second messenger activities. Among the eight analogues synthesized here, only analogue 4 preserves the ability to form a salt bridge between Lys18 and Glu21. However, since these modifications are minor they do not seem to change the amphiphilic character of the C-terminus, allowing these analogues to reach 78-100% stimulation in the adenylate cyclase assay. Biological data from analogues 6-9 supports the idea that position 18 of glucagon may influence binding only, while position 17 may influence both receptor recognition and transduction.

PubMed: 9667960
DOI: 10.1021/jm980084a

実験手法

X-RAY DIFFRACTION (3 Å)