Comparison of the solution structures of angiotensin I & II. Implication for structure-function relationship

Area of Science:

• Biochemistry
• Structural Biology
• Peptide Chemistry

Background:

• Angiotensin peptides (AI and AII) are crucial in cardiovascular regulation.
• Understanding their conformational dynamics is key to their biological activity and receptor interactions.

Purpose of the Study:

• To elucidate the solution structures of angiotensin I (AI) and angiotensin II (AII).
• To investigate the conformational differences between AI and AII.
• To determine the role of the C-terminal dipeptide in their distinct biological functions and receptor binding.

Main Methods:

• 2D 1H-NMR spectroscopy in dimethylsulfoxide (DMSO) and trifluoroethanol/H2O mixtures.
• Nuclear Overhauser Effect (NOE) distance restraints and 3JHNHα coupling constants.
• Restrained energy minimization (REM) refinement for structural modeling.

Main Results:

• Solution structural models of AI and AII were determined in DMSO.
• AI and AII share similar N-terminal conformations but exhibit different C-terminal conformations.
• The His9-Leu10 dipeptide significantly influences C-terminal structure and inter-residue contacts of aromatic residues.
• Ensemble models showed low root-mean-square deviation (RMSD) values for backbone and heavy atoms.

Conclusions:

• The C-terminal conformation, influenced by the His9-Leu10 dipeptide, is critical for the differential binding affinity of AI and AII to the AT1 receptor.
• Structural variations, particularly in side-chain orientation, contribute to the peptides' biological roles.
• This study provides a basis for understanding AII structural differentiation in free and bound states.