title: Triad of polar residues implicated in pH specificity of acidic mammalian chitinase.
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 beta-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.
authors.affiliation: Department of Chemical and Screening Sciences, Structural Biology and Computational Chemistry, Wyeth Research, Cambridge, Massachusetts 02140, USA. aolland@wyeth.com
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Olland
authors.forename: James
authors.initials: J
authors.lastname: Strand
authors.forename: Eleonora
authors.initials: E
authors.lastname: Presman
authors.forename: Robert
authors.initials: R
authors.lastname: Czerwinski
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Rustem
authors.initials: R
authors.lastname: Krykbaev
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schlingmann
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Laura
authors.initials: L
authors.lastname: Lin
authors.forename: Margaret
authors.initials: M
authors.lastname: Fleming
authors.forename: Ron
authors.initials: R
authors.lastname: Kriz
authors.forename: Mark
authors.initials: M
authors.lastname: Stahl
authors.forename: William
authors.initials: W
authors.lastname: Somers
authors.forename: Lori
authors.initials: L
authors.lastname: Fitz
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
mesh_terms: D000117:Acetylglucosamine / Q000031:analogs & derivatives / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000378:metabolism; D016466:CHO Cells; D020134:Catalytic Domain / Q000502:physiology; D002688:Chitinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013379:Substrate Specificity / Q000502:physiology; D014312:Trisaccharides / Q000378:metabolism
chemical_list: D014312:Trisaccharides; C054851:allosamidin; C499254:CHIA protein, human; D002688:Chitinases; D000117:Acetylglucosamine