Programme

O.9 -- Oral, VCTP-45

Date: Monday, 12 October 2020

Time: 16:50 - 17:10

hTSPO monomeric structural model in complex with the PK11195 ligand studied by molecular dynamics simulations

Hien T. T. Lai (1), Giulia Rossetti (2,3,4), Alejandro Giorgetti (2, 5), Paolo Carloni (2, 6), Toan T. Nguyen (1, *), Agata Kranjc (2, *),

(1) VNU Key Laboratory for Multiscale Simulation of Complex Systems, VNU University of Science, Vietnam National University, 334 Nguyen Trai street, Thanh Xuan, Hanoi, 11416, VIETNAM; (2) Institute of Neuroscience and Medicine (INM-9)/Institute for Advanced Simulation (IAS-5), Forschungszentrum Juelich, D-52425 Jülich, Germany; (3) Juelich Supercomputing Center (JSC), Forschungszentrum Juelich, 52428 Juelich, Germany; (4) University Hospital Aachen, RWTH Aachen University, 52078 Aachen, Germany; (5) Department of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, Italy; (6) RWTH Aachen University, Department of Physics, 52078 Aachen, Germany

The translocator protein 18kDa (TSPO) normally present in mitochondria in all human tissues was found to be overexpressed in cancer and at the sites of neuroinflammation processes in cerebral ischemia, Alzheimer ’s, Parkinson’s and Huntington’s diseases and multiple sclerosis. Due to the up-regulated expression it represents an important biomarker to identify the location of neuronal damage and tumor tissue development. The TSPO radiolabeled ligands are used in positron emission tomography (PET) for imaging of inflammatory sites. One of the most commonly used TSPO ligands for studying diagnostics and therapeutics is the 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195) ligand. Despite large number of studies the cellular role of the TSPO is not yet clear and many questions about its structure-function relationships persist. We have built the human TSPO (hTSPO) structural model, since its 3D structure is unknown. With the MD simulations we studied its structural properties in the apo form and when it is in complex with the PK11195 ligand. Our results are in line with the experimental studies: the PK11195 ligand stabilizes the TSPO fold, the most posible way for PK11195 ligand binding is through the membrane and between the TSPO transmembrane helices I and II. We discuss about the interactions between the PK11195 and the hTSPO structural model. Our results add to the knowledge about the structural properties of the TSPO protein and can be of help in search for new diagnostic or therapeutic ligands.

Presenter: Lai Thi Thu Hien

Presentation file: