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J. Biol. Chem., Vol. 280, Issue 9, 8435-8442, March 4, 2005

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The High Resolution Crystal Structure of a Native Thermostable Serpin Reveals the Complex Mechanism Underpinning the Stressed to Relaxed Transition^*

From the ^aProtein Crystallography Unit, Monash Centre for Synchrotron Science, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Faculty of Medicine, ^dVictorian Bioinformatics Consortium, P. O. Box 53, and the ^eAustralian Research Council Centre for Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia and the ^gDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802

Serpins fold into a native metastable state and utilize a complex conformational change to inhibit target proteases. An undesirable result of this conformational flexibility is that most inhibitory serpins are heat sensitive, forming inactive polymers at elevated temperatures. However, the prokaryote serpin, thermopin, from Thermobifida fusca is able to function in a heated environment. We have determined the 1.8 Å x-ray crystal structure of thermopin in the native, inhibitory conformation. A structural comparison with the previously determined 1.5 Å structure of cleaved thermopin provides detailed insight into the complex mechanism of conformational change in serpins. Flexibility in the shutter region and electrostatic interactions at the top of the A -sheet (the breach) involving the C-terminal tail, a unique structural feature of thermopin, are postulated to be important for controlling inhibitory activity and triggering conformational change, respectively, in the native state. Here we have discussed the structural basis of how this serpin reconciles the thermodynamic instability necessary for function with the stability required to withstand elevated temperatures.

Received for publication, September 7, 2004 , and in revised form, December 6, 2004.

The atomic coordinates and structure factors (code 1SNG) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the National Health and Medical Research Council (NHMRC) of Australia, the Australian Research Council, and the state government of Victoria, Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b A Monash University Research Fellow.

^c These authors contributed equally to this work.

^f An Anti-cancer Council of Victoria Research Fellow and Monash University Research Fellow.

^h A Monash University Logan Fellow and R. D. Wright Fellow of the NHMRC.

ⁱ Supported by a Wellcome Trust Senior Research Fellowship in Biomedical Science in Australia. To whom correspondence may be addressed. E-mail: Jamie.Rossjohn{at}med.monash.edu.au.

^j An NHMRC Senior Research Fellow and Monash University Logan Fellow. To whom correspondence may be addressed. E-mail: james.whisstock{at}med.monash.edu.au.

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