10 A niversary of IIMCB

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Sławomir Filipek, PhD, DSc. Habil. DEGREES • DSc. Habil. in medicinal chemistry, Warsaw University, Faculty of Chemistry, 2004 • PhD in theoretical chemistry, Warsaw University, Faculty of Chemistry, 1993 • MSc in quantum chemistry, Warsaw University, Faculty of Chemistry, 1985 POST-DOCTORAL TRAINING 2001, 2002 Visiting Scientist, Department of Ophthalmology, University of Washington, Seattle, WA, USA PROFESSIONAL EMPLOyMENT Since 2002 Head of the Laboratory of Biomodelling, IIMCB 1993-2002 Post-doctoral Fellow, Warsaw University, Faculty of Chemistry 1985-1993 Assistant, Warsaw University, Faculty of Chemistry HONORS, PRIZES, AWARDS 2000-2002 Scientific awards-stipends of Rector of Warsaw University PROFESSIONAL MEMBERSHIPS • Molecular Graphics and Modelling Society • Biophysical Society • Polish Society of Medicinal Chemistry • Polish Bioinformatics Society EDITORIAL BOARD MEMBER • Journal of Bionanoscience • The Open Structural Biology Journal PUBLICATIONS • about 70 publications in primary scientific journals • about 1700 citations • about 1400 citations with IIMCB affiliation (years 2003-2008) 48 Annual Report 2008 Selected publications • Jozwiak K, Zekanowski C, Filipek S. Linear patterns of Alzheimer’s disease mutations along alpha-helices of presenilins as a tool for PS-1 model construction. J Neurochem, 2006; 98:1560-72 • Modzelewska A, Filipek S, Palczewski K, Park PS. Arrestin interaction with rhodopsin: conceptual models. Cell Biochem Biophys, 2006; 46:1-15 • Filipek S, Krzysko KA, Fotiadis D, Liang Y, Saperstein DA, Engel A, Palczewski K. A concept for G protein activation by G protein-coupled receptor dimers: the transducin / rhodopsin interface. Photochem Photobiol Sci, 2004; 3:628-638 • Suda K, Filipek S, Palczewski K, Engel A, Fotiadis D. The supramolecular structure of the GPCR rhodopsin in solution and native disc membranes. Mol Membr Biol, 2004; 21:435-446 • Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes. J Biol Chem, 2003; 278:21655-62 • Fotiadis D, Liang Y, Filipek S, Saperstein DA, Engel A, Palczewski K. Rhodopsin dimers in native disc membranes. Nature, 2003; 421:127-128 • Filipek S, Teller DC, Palczewski K, Stenkamp R. The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors. Annu Rev Biophys Biomol Struct, 2003; 32:375-397 • Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. The role of conserved NPXXY(X)5,6F motif in the rhodopsin ground state and during activation. Proc Natl Acad Sci USA, 2003; 100:2290-95 Publications in 2008-2009 • Austermann J, Nazmi AR, Heil A, Fritz G, Kolinski M, Filipek S, Gerke V. Generation and characterization of a novel, permanently active S100P mutant. Biochim. Biophys. Acta – Mol Cell Res, 2009; accepted • Kannan AM, Renugopalakrishnan V, Filipek S, Li P, Audette GF, Munukutla L. Bio-batteries and bio fuel cells: Leveraging on electronic charge transfer proteins. J Nanosci Nanotechnol, 2009; 9:1665-78 • Thavasi V, Lazarova T, Filipek S, Kolinski M, Querol E, Kumar A, Ramakrishna S, Padros E, Renugopalakrishnan V. Study on the feasibility of bacteriorhodopsin as biophotosensitizer in excitonic solar cell: A first report. J Nanosci Nanotechnol, 2009; 9:1679-87 • Bhatia P, Kolinski M, Moaddel R, Jozwiak K, Wainer IW. Determination and modelling of stereoselective interactions of ligands with drug transporters: a key dimension in the understanding of drug disposition. Xenobiotica, 2008; 38:656-675 • Kolinski M, Filipek S. Molecular dynamics of mu opioid receptor complexes with agonists and antagonists. The Open Struct Biol J, 2008, 2:8-20 • Stephen R, Filipek S, Palczewski K, Sousa MC. Ca 2+ -dependent regulation of phototransduction. Photochem Photobiol, 2008; 84:903-910
• Jozwiak K, Krzysko KA, Bojarski L, Gacia M, Filipek S. Molecular models of the interface between anterior pharynx-defective protein 1 (APH-1) and presenilin involving GxxxG motifs. ChemMedChem, 2008; 3:627-634 • Majewski T, Lee S, Jeong J, Yoon DS, Kram A, Kim MS, Tuziak T, Bondaruk J, Lee S, Park WS, Tang KS, Chung W, Shen L, Ahmed SS, Johnston DA, Grossman HB, Dinney CP, Zhou JH, Harris RA, Snyder C, Filipek S, Narod SA, Watson P, Lynch HT, Gazdar A, Bar-Eli M, Wu XF, McConkey DJ, Baggerly K, Issa JP, Benedict WF, Scherer SE, Czerniak B. Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy. Lab Invest, 2008; 88:694-721 Current Research 1. Studies of activation switches in opioid receptors G protein coupled receptors (GPCRs) interact with very diverse sets of ligands which bind to the transmembrane (TM) segments and sometimes also to the receptor extracellular domains. Each receptor subfamily undergoes a series of conformational rearrangements leading to the binding of a G protein during the activation process. All GPCRs preserved the 7-TM scaffold during evolution but adapted it to different sets of ligands by structure customization. Binding of structurally different agonists requires the disruption of different intramolecular interactions, leading to different receptor conformations and differential effects on downstream signaling proteins. The dynamic character of GPCRs is likely to be essential for their physiological functions, and a better understanding of this molecular plasticity could be important for drug discovery. Experiments suggest that agonist binding and receptor activation occur through a series of conformational intermediates. Transition between these intermediate states involves the disruption of intramolecular interactions that stabilize the basal state of a receptor. Such profound changes are evoked by the action of molecular switches. The switches proposed so far for different GPCRs include the “rotamer toggle switch” involving the CWxPxF sequence on helix TM6, the switch based on the NPxxY(x)(5,6)F sequence linking helices TM7 and H8, the “3-7 lock” interaction connecting TM3 and TM7 (involving the Schiff base-counterion interaction in rhodopsin), and the “ion lock” linking transmembrane helices TM3 and TM6 and employing the E/DRY motif on TM3. Although, in the rhodopsin structure, all these switches are closed (inactive state), in recent crystal structures of b 1 - and b 2 -adrenergic receptor complexes with antagonists and inverse agonists the “ion lock” is open while the “rotamer toggle switch” remains closed. Opioid receptors belong to the family of GPCRs. They are located in the membranes of neurons of the central nervous system and of some types of smooth muscle cells. Due to the important role they play in the human body in controlling pain and stress, modulating immune responses and developing addiction, opioid receptors have been the subject of numerous investigations. There are four types of opioid receptors: µOR, δOR, κOR and the nociceptin/opioid receptor-like 1. There are also additional, pharmacologically classified, subtypes of opioid receptors, though it is believed that they may, at least partly, originate from homodimerization of the four main opioid receptor types and their heterodimerization with other GPCRs. Knowledge of the structural details of receptor activation is absolutely necessary in order to design new drugs with precise action and negligible side effects. Opioid receptors, like other GPCRs, undergo specific structural rearrangements upon activation by agonists. Such processes proceed via several steps ruled by different molecular switches. The first event in opioid receptor activation includes sensing of agonists and antagonists. Agonist binding is the first step in ligand-induced receptor activation. To investigate the relationship between the final movements of a ligand in a receptor binding site and the first steps of the activation process in opioid receptors, we chose a set of rigid ligands with the structural motif of tyramine (p-hydroxyphenethylamine) so that the two parts - the “message” (tyramine) and the “address” - are well distinguished. We used antagonists - naltrexone and b-FNA, and two closely related agonists - morphine and N-methyl-morphine. Using homology modeling, simulated annealing and molecular dynamics of the µ opioid receptor complexes, we proposed distinct binding modes of opioids carrying the same structural motif – tyramine. Although they bind to the same binding pocket and the protonated amine interacts with D3.32, the antagonist’s phenolic OH group tends to bind Y3.33 whereas the agonist’s phenolic OH group tends to bind H6.52 (numbers according to the Ballesteros-Weinstein numbering scheme). All the studied agonists broke the “3-7 lock” (the hydrogen bond D3.32-Y7.43 between TM3 and TM7). Moreover, the antagonist naltrexone, when restrained to bind H6.52, was also able to break this connection (Fig. 1a,b) and, Fig. 1. The structure of naltrexone-µOR complex from unrestrained (ligand in green) and restrained (ligand in orange) MD simulations. During the restrained simulation (a bond between the phenolic OH group of the ligand and H6.52 was fixed) the “3-7 lock” (a hydrogen bond D3.32-Y7.43 between TM3 and TM7) is breaking. (a) view from the extracellular side. (b) a side view of the same structure (author: Sławomir Filipek). Laboratory of Biomodelling 49
Page 1 and 2: INTERNATIONAL INSTITUTE OF MOLECULA
Page 3 and 4: Contents International Institute of
Page 5 and 6: laboratories were launched: the Lab
Page 7 and 8: International Advisory Board Struct
Page 9 and 10: International Advisory Board of the
Page 11 and 12: Description of the Institute’s Ac
Page 13 and 14: Grants 7 th Framework Programme •
Page 15 and 16: ioinformatics to characterize and d
Page 17 and 18: Scientific Meetings and Lectures
Page 19 and 20: Lab Leaders Competitions The princi
Page 21 and 22: Diversity of Funding IIMCB’2008 A
Page 23 and 24: Department of Molecular Biology Lab
Page 25 and 26: Selected publications • Wawrzynow
Page 27 and 28: Fig. 3. Massive overexpression of H
Page 29 and 30: Laboratory of Bioinformatics and Pr
Page 31 and 32: Publications in 2008 • Orlowski J
Page 33 and 34: cross-linking, mass spectrometry, c
Page 35 and 36: Laboratory of Structural Biology MP
Page 37 and 38: • Filipek R, Potempa J, Bochtler
Page 39 and 40: Fig. 4. Overview of peptidoglycan a
Page 41 and 42: Laboratory of Neurodegeneration Lab
Page 43 and 44: Publications in 2008 • Bojarski L
Page 45 and 46: Fig. 2. 21 days in vitro hippocampa
Page 47 and 48: involved in defence against pathoge
Page 49: Laboratory of Biomodelling Lab Lead
Page 53 and 54: Fig. 3. Superimposition of EF-hand
Page 55 and 56: Laboratory of Cell Biology Lab Lead
Page 57 and 58: Description of Current Research The
Page 59 and 60: Fig. 2. Endocytosis of transferrin
Page 61 and 62: Laboratory of Molecular and Cellula
Page 63 and 64: • Swiech L, Perycz M, Malik A, Ja
Page 65 and 66: target of rapamycin). mTOR is a ser
Page 67 and 68: Fig. 3: mTOR inhibition impairs mic
Page 69 and 70: Laboratory of Cell Cortex Mechanics
Page 71 and 72: Research The main goal of the group
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Page 75 and 76: Laboratory of Protein Structure Lab
Page 77 and 78: 1. Integrase superfamily Integrase
Page 79 and 80: Centre for Innovative Bioscience Ed
Page 81 and 82: The Polish Volvox web site (http://
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10 A niversary of IIMCB

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