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Volume 272, Number 7, Issue of February 14, 1997 pp. 3905-3909
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Inhibitory Mechanism of Serpins
MOBILITY OF THE C-TERMINAL REGION OF THE REACTIVE-SITE LOOP

(Received for publication, October 9, 1996, and in revised form, December 2, 1996)

Paul C. R. Hopkins , Wun-Shiang W. Chang , Mark R. Wardell and Stuart R. Stone

From the Department of Haematology, University of Cambridge, Medical Research Council Centre, Hills Road, Cambridge CB2 2QH, United Kingdom

The reactive-site loops of serpins are characterized by a defined mobility where the loop adopts a new secondary structure as an essential part of the inhibitory process. While the importance of mobility in the N-terminal region of the reactive-site loop has been well studied, the role of mobility in the C-terminal portion has not been investigated. The requirements for mobility of the C-terminal portion of the reactive-site loop of alpha 1-antitrypsin were investigated by creating a disulfide bridge between the P'3 residue and residue 283 near the top of strand 2C; this disulfide would restrict the mobility of the C-terminal portion of the reactive-site loop by locking together strands 1 and 2 of the C beta -sheet. The engineered disulfide bond had no effect on the inhibitory activity of alpha 1-antitrypsin, indicating that there is no requirement for mobility in this region of the molecule. Moreover, these results, coupled with those from molecular modeling, indicate that insertion into the A beta -sheet of the intact reactive-loop beyond P12 is not rate-limiting for the formation of the stable complex. The engineered disulfide bond should also prove useful in the creation of more stable serpin variants; for example, such a bond in plasminogen activator inhibitor-1 would prevent it from becoming latent by locking strand 1C onto the C beta -sheet.


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