PMID- 30356695
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2296-2646 (Print)
IS  - 2296-2646 (Electronic)
IS  - 2296-2646 (Linking)
VI  - 6
DP  - 2018
TI  - Computational Studies on the Inhibitor Selectivity of Human JAMM 
      Deubiquitinylases Rpn11 and CSN5.
PG  - 480
LID - 10.3389/fchem.2018.00480 [doi]
LID - 480
AB  - Deubiquitinylases (DUBs) are highly specialized enzymes which are responsible for 
      removal of covalently attached ubiquitin(s) from the targeted proteins. DUBs play 
      an important role in maintaining the protein homeodynamics. Recently, DUBs have 
      emerged as novel therapeutic targets in cancer, inflammation, diabetes, and 
      neurodegeneration. Among the different families of DUBs, the metalloprotease 
      group or JAB1/MOV34/MPR1 (JAMMs) proteases are unique in terms of catalytic 
      mechanism. JAMMs exhibit a Zn(2+)-dependent deubiquitinylase activity. Within the 
      JAMM family, deubiquitinylases Rpn11 and CSN5 are constituents of large 
      bimolecular complexes, namely the 26S proteasome and COP9 signalosome (CSN), 
      respectively. Rpn11 and CSN5 are potential drug targets in cancer and selective 
      inhibitors of both proteins have been reported in the literature. However, the 
      selectivity of JAMM inhibitors (capzimin for RPN11 and CSN5i-3 for CSN5) has not 
      been structurally resolved yet. In the present work, we have explored the binding 
      modes of capzimin and CSN5i-3 and rationalize their selectivity for Rpn11 and 
      CSN5 targets. We found that capzimin interacts with the active site Zn(+2) of 
      Rpn11 in a bidentate manner and also interacts with the residues in the distal 
      ubiquitin binding site. MD simulations studies and binding energy analysis 
      revealed that the selective binding of the inhibitors can be only explained by 
      the consideration of larger heterodimeric complexes of Rpn11 (Rpn8-Rpn11) and 
      CSN5 (CSN5-CSN6). Simulation of these protein-protein complexes is necessary to 
      avoid unrealistic large conformational changes. The selective binding of 
      inhibitors is mainly governed by residues in the distal ubiquitin binding site. 
      This study demonstrates that selective inhibitor binding design for Rpn11 and 
      CSN5 JAMM proteases requires consideration of heterodimeric protein-protein 
      target structures.
FAU - Kumar, Vikash
AU  - Kumar V
AD  - Institute of Experimental and Internal Medicine, Medical Faculty, Otto von 
      Guericke University, Magdeburg, Germany.
AD  - Molecular Simulations and Design Group, Max Planck Institute for Dynamics of 
      Complex Technical Systems, Magdeburg, Germany.
FAU - Naumann, Michael
AU  - Naumann M
AD  - Institute of Experimental and Internal Medicine, Medical Faculty, Otto von 
      Guericke University, Magdeburg, Germany.
FAU - Stein, Matthias
AU  - Stein M
AD  - Molecular Simulations and Design Group, Max Planck Institute for Dynamics of 
      Complex Technical Systems, Magdeburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20181009
PL  - Switzerland
TA  - Front Chem
JT  - Frontiers in chemistry
JID - 101627988
PMC - PMC6189316
OTO - NOTNLM
OT  - computational drug design
OT  - deubiquitinase (DUB)
OT  - ligand binding
OT  - molecular dynamics (MD)
OT  - protein-protein interaction
OT  - selectivities
EDAT- 2018/10/26 06:00
MHDA- 2018/10/26 06:01
PMCR- 2018/01/01
CRDT- 2018/10/26 06:00
PHST- 2018/07/23 00:00 [received]
PHST- 2018/09/20 00:00 [accepted]
PHST- 2018/10/26 06:00 [entrez]
PHST- 2018/10/26 06:00 [pubmed]
PHST- 2018/10/26 06:01 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fchem.2018.00480 [doi]
PST - epublish
SO  - Front Chem. 2018 Oct 9;6:480. doi: 10.3389/fchem.2018.00480. eCollection 2018.