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@ARTICLE{Lai:890496,
      author       = {Lai, Hien T. T. and Giorgetti, Alejandro and Rossetti,
                      Giulia and Nguyen, Toan T. and Carloni, Paolo and Kranjc
                      Pietrucci, Agata},
      title        = {{T}he {I}nterplay of {C}holesterol and {L}igand {B}inding
                      in h{TSPO} from {C}lassical {M}olecular {D}ynamics
                      {S}imulations},
      journal      = {Molecules},
      volume       = {26},
      number       = {5},
      issn         = {1420-3049},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2021-00995},
      pages        = {1250 -},
      year         = {2021},
      abstract     = {The translocator protein (TSPO) is a 18kDa transmembrane
                      protein, ubiquitously present in human mitochondria. It is
                      overexpressed in tumor cells and at the sites of
                      neuroinflammation, thus representing an important biomarker,
                      as well as a promising drug target. In mammalian TSPO, there
                      are cholesterol–binding motifs, as well as a binding
                      cavity able to accommodate different chemical compounds.
                      Given the lack of structural information for the human
                      protein, we built a model of human (h) TSPO in the apo state
                      and in complex with PK11195, a molecule routinely used in
                      positron emission tomography (PET) for imaging of
                      neuroinflammatory sites. To better understand the
                      interactions of PK11195 and cholesterol with this
                      pharmacologically relevant protein, we ran molecular
                      dynamics simulations of the apo and holo proteins embedded
                      in a model membrane. We found that: (i) PK11195 stabilizes
                      hTSPO structural fold; (ii) PK11195 might enter in the
                      binding site through transmembrane helices I and II of
                      hTSPO; (iii) PK11195 reduces the frequency of cholesterol
                      binding to the lower, N–terminal part of hTSPO in the
                      inner membrane leaflet, while this impact is less pronounced
                      for the upper, C–terminal part in the outer membrane
                      leaflet, where the ligand binding site is located; (iv) very
                      interestingly, cholesterol most frequently binds
                      simultaneously to the so-called CRAC and CARC regions in TM
                      V in the free form (residues L150–X–Y152–X(3)–R156
                      and R135–X(2)–Y138–X(2)–L141, respectively).
                      However, when the protein is in complex with PK11195,
                      cholesterol binds equally frequently to the
                      CRAC–resembling motif that we observed in TM I (residues
                      L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We
                      expect that the CRAC–like motif in TM I will be of
                      interest in future experimental investigations. Thus, our MD
                      simulations provide insight into the structural features of
                      hTSPO and the previously unknown interplay between PK11195
                      and cholesterol interactions with this pharmacologically
                      relevant protein.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33652554},
      UT           = {WOS:000628444600001},
      doi          = {10.3390/molecules26051250},
      url          = {https://juser.fz-juelich.de/record/890496},
}