Article

Triad of polar residues implicated in pH specificity of acidic mammalian chitinase

Andrea M. Olland 1 *, James Strand 1, Eleonora Presman 1, Robert Czerwinski 1, Diane Joseph-McCarthy 1, Rustem Krykbaev 2, Gerhard Schlingmann 3, Rajiv Chopra 1, Laura Lin 1, Margaret Fleming 2, Ron Kriz 1, Mark Stahl 1, William Somers 1, Lori Fitz 2, Lidia Mosyak 1

1Department of Chemical and Screening Sciences, Structural Biology and Computational Chemistry, Wyeth Research, Cambridge, Massachusetts 02140 2Department of Inflammation, Wyeth Research, Cambridge, Massachusetts 02140 3Department of Chemical and Screening Sciences, Natural Products Discovery, Wyeth Research, Pearl River, New York 10965

email: Andrea M. Olland (aolland@wyeth.com)

^*Correspondence to Andrea M. Olland, 200 Cambridge Park Drive, Cambridge, MA 02140

Keywords

chitinase • structure • crystallography • asthma • inhibitor • chitin degradation • 3D-structure

Abstract

Acidic mammalian chitinase (AMCase) is a mammalian chitinase that has been implicated in allergic asthma. One of only two active mammalian chinases, AMCase, is distinguished from other chitinases by several unique features. Here, we present the novel structure of the AMCase catalytic domain, both in the apo form and in complex with the inhibitor methylallosamidin, determined to high resolution by X-ray crystallography. These results provide a structural basis for understanding some of the unique characteristics of this enzyme, including the low pH optimum and the preference for the -anomer of the substrate. A triad of polar residues in the second-shell is found to modulate the highly conserved chitinase active site. As a novel target for asthma therapy, structural details of AMCase activity will help guide the future design of specific and potent AMCase inhibitors.

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Received: 3 November 2008; Revised: 18 December 2008; Accepted: 18 December 2008

Digital Object Identifier (DOI)

10.1002/pro.63  About DOI