title: Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations.
abstract: Given that immunoproteasome inhibitors are currently being developed for a variety of potent therapeutic purposes, the unique specificity of an α',β'-epoxyketone peptide (UK101) toward the LMP2 subunit of the immunoproteasome (analogous to β5 subunit of the constitutive proteasome) has been investigated in this study for the first time by employing homology modeling, molecular docking, molecular dynamics simulation, and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations. On the basis of the simulated binding structures, the calculated binding free energies are in qualitative agreement with the corresponding experimental data, and the selectivity of UK101 is explained reasonably. The observed selectivity of UK101 for the LMP2 subunit is rationalized by the requirement for both a linear hydrocarbon chain at the N terminus and a bulky group at the C terminus of the inhibitor, because the LMP2 subunit has a much more favorable hydrophobic pocket interacting with the linear hydrocarbon chain, and the bulky group at the C terminus has a steric clash with the Tyr 169 in β5 subunit. Finally, our results help to clarify why UK101 is specific to the LMP2 subunit of immunoproteasome, and this investigation should be valuable for rational design of more potent LMP2-specific inhibitors.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Beilei
authors.initials: B
authors.lastname: Lei
authors.forename: Mohamed Diwan M
authors.initials: MD
authors.lastname: Abdul Hameed
authors.forename: Adel
authors.initials: A
authors.lastname: Hamza
authors.forename: Marie
authors.initials: M
authors.lastname: Wehenkel
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Muzyka
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Yao
authors.forename: Kyung-Bo
authors.initials: KB
authors.lastname: Kim
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
mesh_terms: D055162:Biocatalysis; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017646:Organosilicon Compounds / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism; D061988:Proteasome Inhibitors; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D017646:Organosilicon Compounds; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D021122:Protein Subunits; C554667:UK 101; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex
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