Dale F. Mierke
|Professor Mierke received his B.S. degrees in Chemistry and in Biological Sciences from the University of California, Irvine in 1984. He received his Ph.D. in 1988 working with Professor Murray Goodman at the University of California, San Diego. Postdoctoral studies took him to the Biopolymer Research Institute in Padova and as a Fulbright Scholar from 1990 - 1993 to work with Horst Kessler at the Technical University of Munich. Professor Mierke joined the faculty at University of Massachusetts, Medical School (Dept Pharmacology) and Clark University (Dept. Chemistry) in 1993. He moved to take up positions in Chemistry and Molecular Pharmacology at Brown University in 1998, then came to Dartmouth in 2007.
Position: Professor of Chemistry
E-Mail: Dale F. Mierke
Research in our laboratory aims to establish the structural basis of the mechanism of action of different peptide hormones. Particular emphasis has been placed on delineation of the interaction of the hormones with their G-protein coupled receptors employing a combination of spectroscopic techniques (NMR, EPR, fluorescence, CD), photoaffinity labeling, and extensive computer simulations. The structures provided from these efforts have facilitated the rational design of molecules with enhanced potency, receptor specificity, and duration of action.
Parathyroid hormone, a major regulator of calcium levels in blood and important target for the treatment of osteoporosis, interacting with the PTH G protein coupled receptor.
Our laboratory is also targeting molecular scaffolds, multidomain proteins that regulate transmembrane receptor trafficking and lifetime as possible targets for cystic fibrosis, osteoporosis, and drug addiction. High-resolution NMR methods provide structural features of the protein domains, both while free and bound to the target receptor. Using novel computational approaches, this information is used to design and optimize small molecule inhibitors of the protein/receptor association.
NMR-derived structure of the PDZ1 domain of synaptic associated protein-97 bound to the C-terminus of the NR2B subunit of the NMDA glutamate receptor.
- Ahn KH, Bertalovitz, AC, Mierke DF, Kendall DA. (2009) Dual role of the second extracellular loop of the cannabinoid receptor 1: ligand binding and receptor localization. Mol Pharmacol. 76 833-42. PMID. 19643997
- Thomas BE, Sharma S, Mierke DF, Rosenblatt M. (2009) Parathyroid Hormone (PTH) and PTH Antagonist Induce Different Conformational Changes in the PTHR1 Receptor. J Bone Miner Res. 24 925-34. PMID. 19063682
- Ahn KH, Pellegrini M, Tsomaia N, Yatawara AK, Kendall DA, Mierke DF. (2009) Structural analysis of the human cannabinoid receptor one carboxyl-terminus identifies two amphipathic helices. Biopolymers 91 565-73. PMID. 19274719
- Thomas, B., Woznica, I., Mierke, DF, Wittelsberger, A., Rosenblatt, M (2008) Conformational changes in the PTH receptor associated with activation by agonist. Mol Endocrinol. 22 1154-62. PMID 18258686
- Monahan, P., Thomas, B., Wittelsberger, A., Mierke, DF, Rosenblatt, M. (2008) Mapping peptide hormone-receptor interactions using a disulfide-trapping approach. Biochemistry.47 5889-95. PMID 18459800
- Famous, KR, Kumarsian, V., Sadri-Kakili, G, Schmidt, HD, Mierke, DF, Cha, J., Pierce, C. (2008) Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking. J Neurosci., 28, 11061-70. PMID 18945913.
- Assil-Kishawi I, Samra TA, Mierke DF, Abou-Samra AB. (2008) Residue 17 of sauvagine cross-links to the first transmembrane domain of corticotropin-releasing factor receptor 1 (CRFR1). J Biol Chem. 283, 35644-51. PMID 18955489
- Wittelsberger, A., Mierke, DF, Rosenblatt, M (2008) Mapping ligand-receptor interfaces: approaching the resolution limit of benzophenone-based photoaffinity scanning. Chem. Biol. Drug Des. 71, 380-383.
- Chatterjee, J.; Mierke, DF.; Kessler, H. (2008) Conformational preference and potential templates of N-methylated cyclic pentaalanine peptides. Chemistry. 14, 1508-17.
- Mierke, DF, Mao, L., Pellegrini, M., Piserchio, A., Plati, J., Tsomia, N. (2007) Structural characterization of the parathyroid hormone receptor domains determinant for ligand binding. Biochem. Soc. Trans. 35, 721-725.
- Stone, SR., Giragossian, C., Mierke, DF, Jackson, GE (2007) Further evidence for a C-terminal structural motif in CCK(2) receptor active peptide hormones. Peptides. 28, 2211-22.
- Dugan AS, Gasparovic ML, Tsomaia N, Mierke DF, O'Hara BA, Manley K, Atwood WJ. (2007) Identification of amino acid residues in BK virus VP1 that are critical for viability and growth. J Virol. 81, 11798-808.
- Stone, SR., Mierke, DF, Jackson, GE (2007) Evidence for a C-terminal structural motif in gastrin and its bioactive fragments in membrane mimetic media. Peptides. 28, 1561-71.
- Yu, J., Lubinsky, D., Tsomia, N., Huang, Z., Taylor, L., Mierke, D.F., Navarro, J., Miraz, O., Polgar, P. (2007) Activation of ERK, JNK, Akt, and G-protein coupled signaling by hybrid angiotensin II AT1/bradykinin B2 receptors expressed in HEK-293 cells. J Cell Biochem. 101, 192-204.
- Plati, J., Tsomia, N., Piserchio, A., Mierke, DF (2007) Structural features of parathyroid hormone receptor coupled to Galpha(s)-protein. Biophys J. 92, 535-40.
- Wolde, M. Fellows, A., Cheng, J., Kivenson, A., Karlson, K., Piserchio, A., Mierke, D.F., Stanton, B.A., Guggino, W.B., Madden, D.R. (2007) Targeting CAL as a negative regulator of D508-CFTR cell-surface expression: An RNAi and structure-based mutagenetic approach. J Biol Chem. 282, 8099-109.