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Biochemistry 1987, 26, 7609-7614 7609 Serine Protease Mechanism: Structure of an Inhibitory Complex of a-Lytic
 

Summary: Biochemistry 1987, 26, 7609-7614 7609
Serine Protease Mechanism: Structure of an Inhibitory Complex of a-Lytic
Protease and a Tightly Bound Peptide Boronic Acidt
Roger Bone,$ Ashok B. Shenvi,s Charles A. Kettner,s and David A. Agard**t
Department of Biochemistry & Biophysics and Howard Hughes Medical Institute, University of California,San Francisco,
San Francisco, California 94143-0448, and Central Research and Development Department, Experimental Station, E. I. du
Pont de Nemours and Company,Inc., Wilmington, Delaware 19898
Received April 17, 1987; Revised Manuscript Received July 24, 1987
ABSTRACT: The structure of the complex formed between a-lytic protease, a serine protease secreted by
Lysobacter enzymogenes, and N-tert-butyloxycarbonylalanylprolylvalineboronic acid (ICi = 0.35 nM) has
been studied by X-ray crystallography to a resolution of 2.0 A. The active-site serine forms a covalent,
nearly tetrahedral adduct with the boronic acid moiety of the inhibitor. The complex is stabilized by seven
hydrogen bonds between the enzyme and inhibitor with additional stabilization arising from van der Waals
interactions between enzyme and inhibitor side chains and the burying of 330 A2of hydrophobic surface
area. Hydrogen bonding between Asp- 102 and His-57 remains intact in the enzyme-inhibitor complex,
and His Ne2is well positioned to donate its hydrogen to the leaving group. Little change in the positions
of protease residues was observed on complex formation (root mean square main chain deviation = 0.13
A), suggesting that in its native state the enzyme is complementary to tetrahedral reaction intermediates
or to the nearly tetrahedral transition state for the reaction.
a-Lytic protease is an extracellular serineprotease produced

  

Source: Agard, David - Department of Biochemistry and Biophysics, University of California at San Francisco

 

Collections: Biotechnology; Biology and Medicine