Molecular basis of the selectivity of the immunoproteasome catalytic subunit LMP2-specific inhibitor revealed by molecular modeling and dynamics simulations.
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.
Lei
Beilei
B
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
Abdul Hameed
Mohamed Diwan M
MD
Hamza
Adel
A
Wehenkel
Marie
M
Muzyka
Jennifer L
JL
Yao
Xiao-Jun
XJ
Kim
Kyung-Bo
KB
Zhan
Chang-Guo
CG
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
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
Blood. 2010 May 20;115(20):4051-60
20110419
J Med Chem. 2009 May 14;52(9):3028-38
19348473
J Am Chem Soc. 2008 Apr 16;130(15):5140-9
18341277
Semin Oncol. 2001 Dec;28(6):607-12
11740818
J Mol Biol. 1998 Apr 17;277(5):1141-52
9571028
Nucleic Acids Res. 2010 Jan;38(Database issue):D142-8
19843607
Nat Rev Mol Cell Biol. 2001 Mar;2(3):179-87
11265247
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9089-90
15967978
Acc Chem Res. 2000 Dec;33(12):889-97
11123888
Bioorg Med Chem Lett. 2005 Apr 1;15(7):1867-71
15780623
Nat Med. 2009 Jul;15(7):781-7
19525961
Annu Rev Biochem. 1998;67:425-79
9759494
J Am Chem Soc. 2009 Aug 26;131(33):11964-75
19642701
J Neurosci. 2003 Dec 17;23(37):11653-61
14684867
Structure. 2002 May;10(5):609-18
12015144
Blood. 2009 May 7;113(19):4667-76
19050304
J Phys Chem B. 2010 Apr 29;114(16):5605-16
20369883
Nat Rev Cancer. 2002 Dec;2(12):927-37
12459731
J Med Chem. 2006 Oct 19;49(21):6177-96
17034125
Biopolymers. 1996 Mar;38(3):305-20
8906967
J Phys Chem B. 2006 Dec 28;110(51):26365-74
17181296
J Med Chem. 2004 Mar 25;47(7):1739-49
15027865
J Phys Chem B. 2009 Nov 12;113(45):15057-66
19831380
Neurobiol Aging. 2006 Jan;27(1):54-66
16298241
Chem Rev. 2009 Apr;109(4):1509-36
19265443
Med Res Rev. 2001 Jul;21(4):245-73
11410931
J Phys Chem B. 2009 Dec 17;113(50):16226-36
19924840
Bioinformatics. 2006 Jan 15;22(2):195-201
16301204
Chem Rev. 2007 Mar;107(3):687-717
17316053
Chem Biol. 2007 Apr;14(4):419-30
17462577
J Phys Chem B. 2005 Mar 17;109(10):4776-82
16851561
Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):10976-83
10500111
Nature. 1997 Apr 3;386(6624):463-71
9087403
Mol Biosyst. 2008 Apr;4(4):280-6
18354780