title: Domain flexibility in aspartic proteinases.
abstract: Comparison of the three-dimensional structures of native endothiapepsin (EC 3.4.23.6) and 15 endothiapepsin oligopeptide inhibitor complexes defined at high resolution by X-ray crystallography shows that endothiapepsin exists in two forms differing in the relative orientation of a domain comprising residues 190-302. There are relatively few interactions between the two parts of the enzyme; consequently, they can move as separate rigid bodies. A translational, librational, and screw analysis of the thermal parameters of endothiapepsin also supports a model in which the two parts can move relative to each other. In the comparison of different aspartic proteinases, the rms values are reduced by up to 47% when the two parts of the structure are superposed independently. This justifies description of the differences, including those between pepsinogen and pepsin (EC 3.4.34.1), as a rigid movement of one part relative to another although considerable distortions within the domains also occur. The consequence of the rigid body movement is a change in the shape of the active site cleft that is largest around the S3 pocket. This is associated with a different position and conformation of the inhibitors that are bound to the two endothiapepsin forms. The relevance of these observations to a model of the hydrolysis by aspartic proteinases is briefly discussed.
authors.affiliation: Department of Crystallography, Birkbeck College, University of London, England.
authors.forename: A
authors.initials: A
authors.lastname: Sali
authors.forename: B
authors.initials: B
authors.lastname: Veerapandian
authors.forename: J B
authors.initials: JB
authors.lastname: Cooper
authors.forename: D S
authors.initials: DS
authors.lastname: Moss
authors.forename: T
authors.initials: T
authors.lastname: Hofmann
authors.forename: T L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D012085:Chymosin / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010434:Pepsin A / Q000737:chemistry / Q000378:metabolism; D010435:Pepsinogens / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D010435:Pepsinogens; D016282:Aspartic Acid Endopeptidases; C042466:Endothia aspartic proteinase; D010434:Pepsin A; D012085:Chymosin