David T. Lodowski, PhD

Assistant Professor
Center for Proteomics and Bioinformatics
School of Medicine
Assistant Professor
Department of Nutrition
School of Medicine
Assistant Professor
Department of Pharmacology
School of Medicine
Graduate Program Director
Systems Biology and Bioinformatics
Department of Nutrition
School of Medicine

Research Information

Research Interests

Starting in graduate school, I successfully initiated structural studies pertaining to the processes of G protein regulated cell signalling primarily utilizing X-ray crystallography and other biochemical and biophysical techniques, culminating in the first structures of the G protein coupled receptor kinases. In my post-doctoral studies I continued to pursue these structures, solving the first structure of an activated G protein coupled receptor, bovine rhodopsin. As I have moved into my independent career as an assistant professor in the Department of Nutrition and the Center for Proteomics and Bioinformatics, I have continued to build upon this foundation, employing high resolution crystallography, mass spectrometry and computational analysis of GPCR structures to answer questions about the mechanism by which GPCRs pass the activation signal through the plasma membrane and the role that ordered water plays in this process. Additional research interests revolve around the utilization of high resolution crystallography to answer fundamental questions about serine protease hydrolysis and the development of peptide based therapeutics for the treatment of blinding diseases.

In addition to my scientific interests, I am also very involved in graduate education, and serve as the graduate program director for the systems biology and bioinformatics program.     

Research Projects

The Lodowski laboratory primarily employs a combination of x-ray crystallography, mass spectrometry and electron microscopy techniques to explore the fundamental mechanisms of signalling and catalysis via protein structure determination.

1. Structural and computational studies of the activation of rhodopsin and other GPCRs to probe the mechanism of GPCR and G protein activation.

G protein coupled receptors are the largest group of cell surface receptors within the human genome and comprise the target of ~30% of all therapeutics used in the clinic. GPCRs play roles in the regulation of heart rate, blood pressure, aspects of metabolism as well as the sensations of sight smell and taste. As a major drug target, the mechanism by which these receptors are activated and inactivated is of great interest. While several structures of activated (agonist-bound) rhodopsin and other GPCRs have been determined, the mechanism by which the agonist-initiated signal propagates through the receptor to initiate nucleotide exchange and consequent activation of Gα subunits is not fully understood.

We have recently determined the highest resolution structure of an activated state opsin (PDB ID:4X1H) determined to date (2.23 Å). In this structure, we observed a continuous polar network of ordered solvent and polar residues which both spans the distance from the chromophore to the G protein binding site and more importantly is not present in the inactive state. This suggests that the establishment of this network plays an integral role in the allosteric mechanism of GPCR activation. This observation has been further borne out by several recent high resolution structures of agonist bound (activated state) structures of ligand activated GPCRs as well. We are also utilizing the combination of mass spectrometry and radiolytic footprinting to  characterize the dynamics of ordered solvent changes within GPCRs and G protein during the activation process.

2. Utilizing ultra-high (sub-Å) crystallography to investigate the catalytic mechanism of bacterial serine proteases.

The conserved catalytic triad formed from serine, histidine and aspartic acid is employed in all forms of life to both hydrolyze bonds or catalyze the addition of varied substrates. It has been estimated that this conserved triad is employed by 30% of all enzymes in the human body, and because of their prevalence and importance these enzymes and their mechanisms of action are amongst the best studied reactions in biochemistry. Despite the level of study and interest in these important enzymes, there are still aspects of catalysis which are not well understood, namely the protonation states of the triad during intermediate catalytic states of the reaction.

Utilizing ultra-high resolution X-ray crystallography as well as neutron crystallography of protein structures which trap catalytic intermediates, we can observe the protonation state changes of both the aspartic acid and histidine. We recently published a 0.83 Å structure of the apo-enzyme state of a bacterial trypsin from streptomyces erythreus (4M7G). We have captured sub-1 Å resolution Michelis-Menten and acyl-enzyme intermediates of this enzyme as well and are in the process of analyzing these structures.

Awards and Honors

K99/R00 Awardee
National Eye Institute
Mt. Sinai Scholar


Recent Publications

  1. Huynh KW, Cohen MR, Jiang J, Samanta A, Lodowski DT, Zhou ZH, Moiseenkova-Bell VY.  Structure of the full-length TRPV2 channel by cryo-EM.Nat Commun. 2016 Mar 29;7:11130. doi: 10.1038/ncomms11130. PMID: 27021073
  2. Blankenship E, Vahedi-Faridi A, Lodowski DT. The High-Resolution Structure of Activated Opsin Reveals a Conserved Solvent Network in the Transmembrane Region Essential for Activation. Structure. 2015 Dec 1;23(12):2358-64. doi: 10.1016/j.str.2015.09.015. Epub 2015 Oct 29. PMID: 26526852
  3. Schmandt N, Velisetty P, Chalamalasetti SV, Stein RA, Bonner R, Talley L, Parker MD, Mchaourab HS, Yee VC, Lodowski DT, Chakrapani S. A chimeric prokaryotic pentameric ligand-gated channel reveals distinct pathways of activation. J Gen Physiol. 2015 Oct;146(4):323-40. doi: 10.1085/jgp.201511478. PMID: 26415570
  4. Lodowski DT, Miyagi M. Analysis of conformational changes in rhodopsin by histidine hydrogen-deuterium exchange. Methods Mol Biol. 2015;1271:123-32. doi: 10.1007/978-1-4939-2330-4_9. PMID: 25697521
  5. Blankenship E, Lodowski DT. Rhodopsin purification from dark-adapted bovine retina. Methods Mol Biol. 2015;1271:21-38. doi: 10.1007/978-1-4939-2330-4_2. PMID: 25697514
  6. Blankenship E, Vukoti K, Miyagi M, Lodowski DT. Conformational flexibility in the catalytic triad revealed by the high-resolution crystal structure of Streptomyces erythraeus trypsin in an unliganded state. Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):833-40. doi: 10.1107/S1399004713033658. PMID: 24598752
  7. Ernst OP, Lodowski DT, Elstner M, Hegemann P, Brown LS, Kandori H. Microbial and animal rhodopsins: structures, functions, and molecular mechanisms. Chem Rev. 2014 Jan 8;114(1):126-63. doi: 10.1021/cr4003769. Epub 2013 Dec 23. Review. PMID: 24364740
  8. Golczak M, Kiser PD, Sears AE, Lodowski DT, Blaner WS, Palczewski K. Structural basis for the acyltransferase activity of lecithin:retinol acyltransferase-like proteins. J Biol Chem. 2012 Jul 6;287(28):23790-807. doi: 10.1074/jbc.M112.361550. Epub 2012 May 17. PMID: 22605381
  9. Salon JA, Lodowski DT, Palczewski K. The significance of G protein-coupled receptor crystallography for drug discovery. Pharmacol Rev. 2011 Dec;63(4):901-37. doi: 10.1124/pr.110.003350. PMID: 21969326
  10. Jastrzebska B, Ringler P, Lodowski DT, Moiseenkova-Bell V, Golczak M, Müller SA, Palczewski K, Engel A. Rhodopsin-transducin heteropentamer: three-dimensional structure and biochemical characterization. J Struct Biol. 2011 Dec;176(3):387-94. doi: 10.1016/j.jsb.2011.08.016. PMID: 21925606


Doctor of Philosophy
Molecular Biology
University of Texas at Austin
Bachelor of Science
Cell and Molecular Biology

Additional Information

Protein Structures Determined: