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Department Research Activities

Abby Parrill, Atkins Professor

Computational Bioorganic Chemistry

Research interests in the Parrill group are in the areas broadly described as computational structural biology and rational ligand design. The rapid growth of experimental techniques that probe the three-dimensional structure of biologically important structures such as proteins have provided a wealth of information that can be used to study protein structure and design ligands that will bind to these molecules. Such ligands can be used to gather additional information that is useful for the optimization of drugs and molecules with other important functions. Specific projects related to both computational structural biology and rational ligand design involve studies of the interactions between existing or newly designed ligands with interesting biological targets. Our group is currently working with several different protein systems. Some of these projects are collaborations with experimental researchers.

The protein systems under active research in our group are:



Interactions of Phospholipids with their Cellular Receptors:

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Phospholipid growth factors, including sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA), are involved in signaling processes leading to cellular proliferation and motility, wound healing, and angiogenesis. These growth factors exert their effects through receptors embedded in the cellular membrane. Experimental characterization of these cellular receptors is extremely difficult, and modeling methods can provide significant guidance to experimental work. We have developed models of the cellular receptors both alone and in complex with their ligands. These models have been used to guide experimental site-directed mutagenesis studies performed in the laboratory of Gabor Tigyi (UT-Memphis). The models are in agreement with binding studies on these mutants that have been performed in the laboratories of Sarah Spiegel (Georgetown University), Gabor Tigyi (University of Tennessee Health Sciences Center), James VanBrocklyn (Ohio State University), Hugh Rosen (The Scripps Research Institute) and Yasuyuki Igarashi (Hokkaido University).  The models have more recently been used in the design of peptides that will adopt conformations analogous to those of the extracellular loops of these receptors in aqueous solution for characterization using NMR and CD spectroscopy in collaboration with Richard Kriwacki (St. Jude Children's Research Hospital).  We are now poised to use these models to identify novel, highly potent, and receptor subtype-selective agonists and antagonists of these receptors.  These studies are funded by the National Institutes of Health.


Selected Publications:

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1.    Norman, D.D.; Ibezim, A.; Scott, W.E.; White, S.; Parrill, A.L.; Baker, D.L.  Autotaxin Inhibition:  Development and Application of Computational Tools to Identify Site-Selective Lead Compounds”, Bioorg. & Med. Chem., 2013,21(17), 5548-5560.

2.    Bukiya, A.; McMillan, J.; Fedinec, A.; Patil, S.; Miller, D.; Leffler, C.; Parrill, A.; Dopico, A.  “Cerebrovascular Dilation Via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1 Subunit by a Novel Nonsteroidal Agent”, Mol. Pharmacol., 2013, 83(5), 1030-1044.

3.    Young, J.K.; Clayton, B.T.; Kikonyogo, A.; Pham, T.C.T.; Parrill, A.L.  “Structure Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint”, Int. J. Mol. Sci., 2013, 14, 2788-2807.  Doi:10.3390/ijms14022788

4.    Parrill, A.L.; Tigyi, G.  “Integrating the puzzle pieces:  The current atomistic picture of phospholipid-G protein coupled receptor interactions”, Biochim. Biophys. Acta, 2013, 1831(1), 2-12.  PMID:  22982815

5.    Ruddick, K.; Parrill, A.L.; Petersen, R.  “Introductory Molecular Orbital Theory:  An Honors General Chemistry Computational Lab as Implemented in ChemBio3D Ultra 12.0”, J. Chem. Educ., 2012, 89(11), 1358-1363.  DOI:  10.1021/ed2003719

6.    Parrill, A.L.; Lima, S.; Spiegel, S. “Structure of the first sphingosine 1-phosphate receptor”, Sci. Signal., 2012, 5, pe23.  [abstract, full-text, reprint]

7.    Singh, A.K.; McMillan, J.; Bukiya, A.N.; Burton, B.; Parrill, A.L.; Dopico, A.M.  “Multiple cholesterol recognition/interaction amino acid consensus (CRAC) motifs in the cytosolic C tail of the slo1 subunit determine cholesterol sensitivity of Ca2+ and voltage-gated K+ (BK) channels”, J. Biol. Chem., 2012, 287:20509-20521, DOI:10.1074/jbc.M112.356261.

8.    Parrill, A.L.  “Comparative modeling of lipid receptors”, Chapter 12 in Membrane Protein Structure:  Methods and Protocols, Methods in Molecular Biology Series, edited by N. Vaidehi and Klein-Seetharaman, J.; 2012, vol. 914, 207-218.  DOI 101007/978-1-62703-023-6_12.

9.    Bukiya, A.N.; Singh, A.K.; Parrill, A.L.; Dopico, A.M.  “The steroid interaction site in transmembrane domain 2 of the large conductance, voltage- and calcium-gated potassium (BK) channel accessory β1 subunit”, Proc. Natl. Acad. Sci. USA, 2011, 108:50, 20207-20212.  PMID:  22123969

10. Parrill, A.L.; Wanjala, I.W.; Pham, T.C.T.; Baker, D.L.  “Computational Identification and Experimental Characterization of Substrate Binding Determinants of Nucleotide Pyrophosphatase/Phosphodiesterase 7”, BMC Biochemistry, 2011, 12:65.  doi:10.1186/1471-2091-12-65

11. Mize, C.D.; Abbott, A.M.; Gacasan, S.B.; Parrill, A.L.; Baker, D.L.  “Ligand-Based Autotaxin Pharmacophore Models Reflect Structure-Based Docking Results”, J. Mol. Graph. Modelling, 2011, 31, 76-86.

  1. Parrill, A.L.; Echols, U.; Nguyen, T.; Pham, T.C.T.; Hoeglund, A.; Baker, D. L. “Virtual Screening Approaches for the Identification of Non-Lipid Autotaxin Inhibitors”, Bioorg. Med. Chem., 2008, 16(4), 1784-1795.
  2. Pham, T. C. T.; Kriwacki, R. W.; Parrill, A. L. “Peptide Design and Structural Characterization of a GPCR Loop Mimetic”, Biopolymers, 2007, 86(4), 298-310.
  3. Naor, M.M.; Walker, M.D.; Van Brocklyn, J.R.; Tigyi, G.; Parrill, A.L. “Sphingosine 1-Phosphate pKa and Binding Constants: Intramolecular and Intermolecular Influences”, J. Mol. Graph. Modelling, 2007, 26(2), 519-528.
  4. Tsukahara, T.; Tsukahara, R.; Yasuda, S.; Makarova, N.; Valentine, W.J.; Allison, P.; Yuan, H.; Baker, D.L.; Li, Z.; Bittman, R.; Parrill, A.; Tigyi, G.  Different Residues Mediate Recognition of 1-O-Oleyllysophosphatidic Acid and Rosiglitazone in the Ligand Binding Domain of Peroxisome Proliferator Activated Receptor Gamma, J. Biol. Chem. (2006), 281(6), 3398-3407.
  5. Durgam, G.G.; Tsukahara, R.; Makarova, N.; Walker, M.D.; Fujiwara, Y.; Pigg, K.R.; Baker, D.L.; Sardar, V.M.; Parrill, A.L.; Tigyi, G.; Miller, D.D.  Synthesis and Pharmacological Evaluation of Second-Generation Phosphatidic Acid Derivatives as Lysophosphatidic Acid Receptor Ligands, Bioorg. Med. Chem. Lett. (2006), 16(3), 633-640.
  6. Parrill, A.L.  Structural Characteristics of Lysophosphatidic Acid Biological Targets.  Biochem. Soc. Trans.  (2005), 33(Pt. 6), 1366-1369.
  7. Fujiwara, Y.; Sardar, V.; Tokumura, A.; Baker, D.; Murakami-Murofushi, K.; Parrill, A.; Tigyi, G.  Identification of Residues Responsible for Ligand Recognition and Regioisomeric Selectivity of Lysophosphatidic Acid Receptors Expressed in Mammalian Cells, J. Biol. Chem., (2005), 280(41), 35038-35050.
  8. Jo, E.; Sanna, M.G.; Gonzalez-Cabrera, P.J.; Thangada, S.; Tigyi, G.; Osborne, D.A.; Hla, T.; Parrill, A.L.; Rosen, H.  S1P1-selective in vivo-active agonists from high throughput screening: Off-the-shelf chemical probes of receptor interactions, signaling and fate, Chemistry & Biology, (2005), 12(6), 703-715.
  9. Inagaki, Y.; Pham, T.C.T.; Fujiwara, Y.; Kohno, T.; Osborne, D.A.; Igarashi, Y.; Tigyi, G.; Parrill, A.L. Sphingosine-1-Phosphate Analog Recognition and Selectivity at S1P4 within the Endothelial Differentiation Gene Family of Receptors, Biochem. J., (2005), 389(Pt. 1), 187-195.
  10. Yuan, H.; Parrill, A.  Cluster Analysis and three-dimensional QSAR studies of HIV-1 integrase inhibitors, Journal of Molecular Graphics and Modelling, (2005), 23, 317-328.
  11. Kumar, N.; Tomar, A.; Parrill, A.L.; Khurana, S. Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin, J. Biol. Chem., (2004), 279(43), 45036-45046.
  12. Parrill, A. L.; Sardar, V. M.; Yuan, H. “Sphingosine 1-phosphate and lysophosphatidic acid receptors: Agonist and antagonist binding and progress toward development of receptor-specific ligands” Sem. Cell Devel. Biol., 2004, 15(5), 467-476.
  13. Holdsworth, G.; Osborne, D.A.; Pham, T.C.T.; Fells, J. I.; Hutchinson, G.; Milligan, G.; Parrill, A.L., “A single amino acid determines preference between phospholipids and reveals length restriction for activation of the S1P4 receptor”, BMC Biochemistry, 2004, 5:12.
  14. Virag, T.; Elrod, D. B.; Liliom, K.; Sardar, V. M.; Parrill, A.L.; Yokoyama, K.; Durgam, G.; Deng, W.; Miller, D. D.; Tigyi, G., “Fatty Alcohol Phosphates are Subtype-Selective Agonists and Antagonists of LPA Receptors”, Mol. Pharmacol., 2003, 63(5), 1032-1042.
  15. Parrill, A. L. “HIV-1 Integrase Inhibition: Binding Sites, Structure Activity Relationships and Future Perspectives”, Curr. Med. Chem., 2003, 10, 1811-1824.
  16. Yuan, Y.; Parrill, A. L. “QSAR Studies of HIV-1 Integrase Inhibition”, Bioorg. Med. Chem., 2002, 10(12), 4169-4183.
  17. Sardar, V. M.; Bautista, D. L.; Fischer, D. J.; Yokoyama, K.; Nusser, N.; Virag, T.; Wang, D.; Baker, D. L.; Tigyi, G. and Parrill, A. L. “Molecular Basis for Lysophosphatidic Acid Receptor Antagonist Selectivity”, Biochim. Biophys. Acta, 2002, 1582(1-3), 310-318.
  18. Wang, D.; Lorincz, Z.; Bautista, D.L.; Liliom, K.; Tigyi, G.; Parrill, A.L. “A Single Amino Acid Determines Lysophospholipid Specificity of the S1P1 (EDG1) and LPA1 (EDG2) Phospholipid Growth Factor Receptors”, J. Biol. Chem., 2001, 276(52), 49213-49220.
  19. Roaten, J.B.; Kazanietz, M. G.; Sweatman, T.W.; Lothstein, L.; Israel, M.; Parrill, A.L. “Molecular Models of N-benzyladriamycin-14-valerate (AD 198) in Complex with the Phorbol Ester-Binding C1b Domain of Protein Kinase C-d”, J. Med. Chem, 44(7), 2001, 1028-1034.
  20. Parrill, A.L.; Wang, D.-A.; Bautista, D.L.; Van Brocklyn, J.R.; Lorincz, Z.; Fischer, D.J.; Baker, D.L.; Liliom, K.; Spiegel, S.; Tigyi, G. "Identification of Edg1 Receptor Residues that Recognize Sphingosine 1-Phosphate", J. Biol. Chem., 2000, 275, 39379-39384.

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