PMID- 26190207
OWN - NLM
STAT- MEDLINE
DCOM- 20160803
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 5
DP  - 2015 Jul 20
TI  - Insights into the key interactions between human protein phosphatase 5 and 
      cantharidin using molecular dynamics and site-directed mutagenesis bioassays.
PG  - 12359
LID - 10.1038/srep12359 [doi]
LID - 12359
AB  - Serine/threonine protein phosphatase 5 (PP5) is a promising novel target for 
      anticancer therapies. This work aims to uncover the key interactions at the 
      atomic level between PP5 and three inhibitors (cantharidin, norcantharidin and 
      endothall). We found that, unlike previous report, Arg 100 contributes less to 
      PP5-inhibitor binding, and the residues His 69, Asn 128, His 129, Arg 225, His 
      252 and Arg 250 are of importance to PP5-inhibitor binding. The hydrophobic 
      interactions established between the residues Val 254, Phe 271 and Tyr 276, 
      especially Glu 253, are very important to enhance the inhibitive interaction. We 
      suggested that, to increase the inhibitory activity, the interactions of 
      inhibitor with three negatively charged unfavorable interaction residues, Asp 99, 
      Glu 130 and Asp 213, should be avoided. However, the interactions of inhibitor 
      with favorable interaction residue Arg 250 could enhance the inhibitory activity. 
      The Manganese ion 2 (MN2) unfavorably contribute to the total interaction free 
      energies. The coordination between MN2 and chemical group of inhibitor should be 
      eliminated. This work provides insight into how cantharidin and its analogs bind 
      to PP5c at the atomic level and will facilitate modification of cantharidin-like 
      chemicals to rationally develop more specific and less cytotoxic anti-cancer 
      drugs.
FAU - Liu, Ji-Yuan
AU  - Liu JY
AD  - Key Laboratory of Plant Protection Resources &Pest Management of the Ministry of 
      Education, Northwest A&F University, Yangling 712100, Shaanxi, China.
FAU - Chen, Xi-En
AU  - Chen XE
AD  - Key Laboratory of Plant Protection Resources &Pest Management of the Ministry of 
      Education, Northwest A&F University, Yangling 712100, Shaanxi, China.
FAU - Zhang, Ya-Lin
AU  - Zhang YL
AD  - Key Laboratory of Plant Protection Resources &Pest Management of the Ministry of 
      Education, Northwest A&F University, Yangling 712100, Shaanxi, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150720
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Ligands)
RN  - 0 (Nuclear Proteins)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.3.16 (protein phosphatase 5)
RN  - IGL471WQ8P (Cantharidin)
RN  - OF5P57N2ZX (Alanine)
SB  - IM
MH  - Alanine/genetics
MH  - Cantharidin/*chemistry/pharmacology
MH  - Drug Design
MH  - Enzyme Inhibitors/*chemistry/pharmacology
MH  - Humans
MH  - Hydrogen Bonding
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - *Molecular Dynamics Simulation
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Nuclear Proteins/antagonists & inhibitors/*chemistry/genetics
MH  - Phosphoprotein Phosphatases/antagonists & inhibitors/*chemistry/genetics
MH  - Protein Binding
MH  - Structure-Activity Relationship
PMC - PMC4507179
EDAT- 2015/07/21 06:00
MHDA- 2016/08/04 06:00
PMCR- 2015/07/20
CRDT- 2015/07/21 06:00
PHST- 2015/02/08 00:00 [received]
PHST- 2015/05/05 00:00 [accepted]
PHST- 2015/07/21 06:00 [entrez]
PHST- 2015/07/21 06:00 [pubmed]
PHST- 2016/08/04 06:00 [medline]
PHST- 2015/07/20 00:00 [pmc-release]
AID - srep12359 [pii]
AID - 10.1038/srep12359 [doi]
PST - epublish
SO  - Sci Rep. 2015 Jul 20;5:12359. doi: 10.1038/srep12359.