PMID- 30521141
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20200316
IS  - 1097-0134 (Electronic)
IS  - 0887-3585 (Print)
IS  - 0887-3585 (Linking)
VI  - 87
IP  - 2
DP  - 2019 Feb
TI  - Interplay of cysteine exposure and global protein dynamics in small-molecule 
      recognition by a regulator of G-protein signaling protein.
PG  - 146-156
LID - 10.1002/prot.25642 [doi]
AB  - Regulator of G protein signaling (RGS) proteins play a pivotal role in regulation 
      of G protein-coupled receptor (GPCR) signaling and are therefore becoming an 
      increasingly important therapeutic target. Recently discovered thiadiazolidinone 
      (TDZD) compounds that target cysteine residues have shown different levels of 
      specificities and potencies for the RGS4 protein, thereby suggesting intrinsic 
      differences in dynamics of this protein upon binding of these compounds. In this 
      work, we investigated using atomistic molecular dynamics (MD) simulations the 
      effect of binding of several small-molecule inhibitors on perturbations and 
      dynamical motions in RGS4. Specifically, we studied two conformational models of 
      RGS4 in which a buried cysteine residue is solvent-exposed due to side-chain 
      motions or due to flexibility in neighboring helices. We found that TDZD 
      compounds with aromatic functional groups perturb the RGS4 structure more than 
      compounds with aliphatic functional groups. Moreover, small-molecules with 
      aromatic functional groups but lacking sulfur atoms only transiently reside 
      within the protein and spontaneously dissociate to the solvent. We further 
      measured inhibitory effects of TDZD compounds using a protein-protein interaction 
      assay on a single-cysteine RGS4 protein showing trends in potencies of compounds 
      consistent with our simulation studies. Thermodynamic analyses of RGS4 
      conformations in the apo-state and on binding to TDZD compounds revealed links 
      between both conformational models of RGS4. The exposure of cysteine side-chains 
      appears to facilitate initial binding of TDZD compounds followed by migration of 
      the compound into a bundle of four helices, thereby causing allosteric 
      perturbations in the RGS/Galpha protein-protein interface.
CI  - (c) 2018 Wiley Periodicals, Inc.
FAU - Mohammadi, Mohammadjavad
AU  - Mohammadi M
AD  - Department of Chemical Engineering, University of New Hampshire, Durham, New 
      Hampshire.
FAU - Mohammadiarani, Hossein
AU  - Mohammadiarani H
AD  - Department of Chemical Engineering, University of New Hampshire, Durham, New 
      Hampshire.
FAU - Shaw, Vincent S
AU  - Shaw VS
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan.
FAU - Neubig, Richard R
AU  - Neubig RR
AD  - Department of Pharmacology and Toxicology, Michigan State University, East 
      Lansing, Michigan.
FAU - Vashisth, Harish
AU  - Vashisth H
AUID- ORCID: 0000-0002-2087-2880
AD  - Department of Chemical Engineering, University of New Hampshire, Durham, New 
      Hampshire.
LA  - eng
GR  - P20 GM113131/GM/NIGMS NIH HHS/United States
GR  - T32 GM092715/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20181226
PL  - United States
TA  - Proteins
JT  - Proteins
JID - 8700181
RN  - 0 (RGS Proteins)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Thiadiazoles)
RN  - 175335-35-0 (RGS4 protein)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Animals
MH  - Cysteine/*chemistry/metabolism
MH  - GTP-Binding Proteins/*chemistry/metabolism
MH  - Humans
MH  - Molecular Conformation
MH  - *Molecular Dynamics Simulation
MH  - Protein Binding/drug effects
MH  - Protein Domains
MH  - Protein Structure, Secondary
MH  - RGS Proteins/*chemistry/metabolism
MH  - Receptors, G-Protein-Coupled/*chemistry/metabolism
MH  - Signal Transduction/drug effects
MH  - Small Molecule Libraries/*chemistry/metabolism/pharmacology
MH  - Thiadiazoles/chemistry/metabolism
PMC - PMC6387623
MID - NIHMS1005123
OTO - NOTNLM
OT  - Thiadiazolidinone inhibitors
OT  - allosteric inhibitors
OT  - drug discovery
OT  - molecular dynamics
OT  - protein-protein interactions
OT  - regulators of G-protein signaling
EDAT- 2018/12/07 06:00
MHDA- 2020/03/17 06:00
PMCR- 2020/02/01
CRDT- 2018/12/07 06:00
PHST- 2018/07/09 00:00 [received]
PHST- 2018/11/07 00:00 [revised]
PHST- 2018/11/29 00:00 [accepted]
PHST- 2018/12/07 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2018/12/07 06:00 [entrez]
PHST- 2020/02/01 00:00 [pmc-release]
AID - 10.1002/prot.25642 [doi]
PST - ppublish
SO  - Proteins. 2019 Feb;87(2):146-156. doi: 10.1002/prot.25642. Epub 2018 Dec 26.