Atomic structure of the trypsin-A90720A complex: a unified approach to structure and function

• Published in: Chemistry & biology 1994-10, Vol.1 (2), p.113-117
• Main Authors: Y. Lee, Angela, A. Smitka, Tim, Bonjouklian, Rosanne, Clardy, Jon
• Format: Article
• Language: English
• Subjects: Animals; Cattle; crystal structure; Crystallography, X-Ray; cyclic peptide; Microchaete loktakensis; Molecular Conformation; Peptides, Cyclic - chemistry; proteinase inhibitor; serine proteinase; Solubility; Trypsin - chemistry; Trypsin Inhibitors - chemistry
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/1074-5521(94)90049-3

Background: A90720A is a potent serine proteinase inhibitor produced by the terrestrial blue-green alga Microchaete loktakensis. Most of its structure has been defined by spectroscopic and degradative studies, but the configurations of several stereochemical centers are unknown, and its mode of inhibition of serine proteinases is not understood. We therefore examined the structure of the compound in a complex with trypsin. Results: We have crystallized the bovine trypsin-A90720A complex and determined its three-dimensional structure at 1.90 Å resolution using single crystal X-ray diffraction. The structure of the bound inhibitor is clearly shown in the electron density. The structure defines the absolute stereostructure of A90720A, establishes its bound conformation and illuminates its mode of inhibition. Conclusions: A90720A interacts with trypsin in a substrate-like manner through an extensive series of hydrogen bonds, hydrophobic interactions and steric complementarity. The compound uses a mixture of peptidal and nonpeptidal elements to imitate the canonical conformation of the exposed binding loop of ‘small’ proteinase inhibitors.