Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY
Volume 1477, Issue 1-2, Pages 324-337Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0167-4838(99)00284-8
Keywords
chymotrypsin; transition state complex; standard mechanism, canonical protein inhibitor of serine proteinase; family of proteinase inhibitor; turkey ovomucoid third domain; reactive site peptide bond
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Funding
- NIGMS NIH HHS [GM10831] Funding Source: Medline
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Proteinases perform many beneficial functions that are essential to life, but they are also dangerous and must be controlled. Here we focus on one of the control mechanisms: the ubiquitous presence of protein proteinase inhibitors. We deal only with a subset of these: the standard mechanism, canonical protein inhibitors of serine proteinases. Each of the inhibitory domains of such inhibitors has one reactive site peptide bond, which serves all the cognate enzymes as a substrate. The reactive site peptide bond is in a combining loop which has an identical conformation in all inhibitors and in all enzyme-inhibitor complexes. There are at least 18 families of such inhibitors. They all share the conformation of the combining loops but each has its own global three-dimensional structure. Many three-dimensional structures of enzyme-inhibitor complexes were determined. They are frequently used to predict the conformation of substrates in very short-lived enzyme-substrate transition state complexes. Turkey ovomucoid third domain and eglin c have a Leu residue at P-1. In complexes with chymotrypsin, these P1 Leu residues assume the same conformation. The relative free energies of binding of P1 Leu (relative to either PI Gly or P1 Ala) are within experimental error, the same for complexes of turkey ovomucoid third domain, eglin c, PI Leu variant of bovine pancreatic trypsin inhibitor and of a substrate with chymotrypsin. Therefore, the PI Leu conformation in transition state complexes is predictable. In contrast, the conformation of PI Lys(+) is strikingly different in the complexes of Lys(18) turkey ovomucoid third domain and of bovine pancreatic trypsin inhibitor with chymotrypsin. The relative free energies of binding are also quite different. Yet, the relative free energies of binding are nearly identical for Lys(+) in turkey ovomucoid third domain and in a substrate, thus allowing us to know the structure of the latter. Similar reasoning is applied to a few other systems. (C) 2000 Elsevier Science B.V. All rights reserved.
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