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J. Biol. Chem., Vol. 280, Issue 18, 17953-17960, May 6, 2005

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The Importance of Dynamic Effects on the Enzyme Activity

X-RAY STRUCTURE AND MOLECULAR DYNAMICS OF ONCONASE MUTANTS^*

Antonello Merlino, Lelio Mazzarella¶||, Anna Carannante, Anna Di Fiore, Alberto Di Donato**, Eugenio Notomista**, and Filomena Sica¶

From the Dipartimento di Chimica, Università degli Studi di Napoli "Federico II," Via Cynthia, 80126 Napoli, Centro Regionale di Competenza-Bioteknet, Complesso Ristrutturato S. Andrea delle Dame, Via L. De Crecchio, 7-80138 Napoli, ^¶Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Via Mezzocannone 6, 80134 Napoli, and ^**Dipartimento di Biologia Strutturale e Funzionale, Università "Federico II," Via Cynthia, 80126 Napoli, Italy

Onconase (ONC), a member of the RNase A superfamily extracted from oocytes of Rana pipiens, is an effective cancer killer. It is currently used in treatment of various forms of cancer. ONC antitumor properties depend on its ribonucleolytic activity that is low in comparison with other members of the superfamily. The most damaging side effect from Onconase treatment is renal toxicity, which seems to be caused by the unusual stability of the enzyme. Therefore, mutants with reduced thermal stability and/or increased catalytic activity may have significant implications for human cancer chemotherapy. In this context, we have determined the crystal structures of two Onconase mutants (M23L-ONC and C87S,des103–104-ONC) and performed molecular dynamic simulations of ONC and C87S,des103–104-ONC with the aim of explaining on structural grounds the modifications of the activity and thermal stability of the mutants. The results also provide the molecular bases to explain the lower catalytic activity of Onconase compared with RNase A and the unusually high thermal stability of the amphibian enzyme.

Received for publication, February 4, 2005

^* This work was supported by research grants Regione Campania "Legge 5" and by an FIRB grant from the Italian Ministero dell'Istruzione e dell'Università. 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.

The atomic coordinates and structure factors (codes 1YV4, 1YV6, and 1YV7) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^|| To whom correspondence may be addressed: Dipartimento di Chimica, Università di Napoli "Federico II" Complesso Universitario di Monte Sant' Angelo, Via Cynthia, 80126 Napoli, Italy. Fax: 39-081-674090; E-mail: lelio.mazzarella{at}unina.it. To whom correspondence may be addressed: Dipartimento di Chimica, Università di Napoli "Federico II" Complesso Universitario di Monte Sant' Angelo, Via Cynthia, 80126 Napoli, Italy. Fax: 39-081-674090; E-mail: filomena.sica{at}unina.it.

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