title: Probing structural determinants distal to the site of hydrolysis that control substrate specificity of the 20S proteasome.
abstract: The 20S proteasome is a large multicomponent protease complex. Relatively little is known about the mechanisms that control substrate specificity of its multiple active sites. We present here the crystal structure at 2.95 A resolution of a beta2-selective inhibitor (MB1) bound to the yeast 20S proteasome core particle (CP). This structure is compared to the structure of the CP bound to a general inhibitor (MB2) that covalently modified all three (beta1, beta2, beta5) catalytic subunits. These two inhibitors differ only in their P3 and P4 residues, thereby highlighting binding interactions distal to the active site threonine that control absolute substrate specificity of the complex. Comparisons of the CP-bound structures of MB1, MB2, and the natural products epoxomycin and TMC-95A also provide information regarding general binding modes for several classes of proteasome inhibitors.
authors.affiliation: Max Planck Institut für Biochemie, D-82152, Martinsried, Germany. groll@biochem.mpg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Tamim
authors.initials: T
authors.lastname: Nazif
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D001665:Binding Sites; D003461:Crystallography; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D021122:Protein Subunits; D029701:Saccharomyces cerevisiae Proteins; D013450:Sulfones; C408291:TMC-95A; C009873:divinyl sulfone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin