Elias Lolis, PhD
Research & Publications
Biography
News
Research Summary
We are interested in understanding the mechanism of action of proteins involved in infectious disease, inflammation, and cancer using a variety of techniques including structural biology, yeast genetics, and signal transduction. For example, we determined the three-dimensional structure of two chemokines, human CXCL12 and herpesvirus-8 vMIP-II. We are currently using variety of methods to determine how these proteins interact with theG-protein coupled receptor, CXCR4, a HIV-1 co-receptor and a therapeutic target for cancer metastasis. In collaboration with Demetrios Braddock (Departmentof Pathology), we determined the structure of FIR, a protein that counter-regulates the transcription of the oncogene c-myc. In the area of inflammation we have been studying the signaling mechanism by which macrophage migration inhibitory factor (MIF) exerts its pro-inflammatory effects. We have determined the structure of MIF in the presence of small molecule inhibitors and are studying these inhibitors in mouse models of autoimmunity, inflammation, or infectious diseases.
Specialized Terms: Cancer; Inflammation; Infectious disease; Macromolecular X-ray crystallography; Signaling pathways; Drug design; High throughput screening (HTPS)
Extensive Research Description
We are generally interested in understanding the biology, structure, mechanism of action, and pharmacology (inhibition) of proteins that lead to infectious disease, inflammation, and cancer. Our studies are multidisciplinary and include structural biology (X-ray crystallography or NMR), high throughput screening and/or inhibitor design, structure-activity relationships, mutational analysis, the use of a strain of yeast as a model system for chemokines and their receptors, and animal models of disease.
Our current studies include structure-function relationships of chemokines, a family of secreted proteins that recruit immune cells to the site of infection or tissue injury and function by activating specific G-protein coupled receptors. CXCL12 (SDF-1alpha) and vMIP-II/vCCL2 are an agonist and antagonist, respectively, for the GPCR CXCR4, a co-receptor for HIV-1. This receptor also mediates metastasis in a number of cancers, and a C-terminal mutation responsible for an immunosuppressive disease known as WHIM syndrome. Importantly, CXCR4 is the target for Plerixafor, a drug used in peripheral stem cell transplantation. We have determined the structures of CXCL12 and vMIP-II/vCCL2 and are working towards understanding their interactions CXCR4 at high resolution. We are also using random mutagenesis combined with yeast genetics to define smaller peptides with agonist, partial agonist, or antagonist activity.
The other major project is MIF. Inhibition of this "cytokine" MIF by neutralizing antibodies leads to therapeutic efficacy in animal models of sepsis, arthritis, and glomerulonephritis. This protein also inhibits the apoptotic activity of p53. The three-dimensional structure of MIF revealed a striking similarity with two microbial enzymes, including the presence of an enzyme-like crevice with catalytic functional groups. We are now attempting to determine the role of this site in inflammatory diseases and cancer. Interestingly, parasites also express and secrete this protein. In collaborative studies with Drs. Michael Cappello and Richard Bucala, we have determined the structure of MIF expressed from hookworm and Leishmania major, used high throughput screening, and structure-activity relationships to identify compounds with sub-micromolar Ki's.
Other projects include determining the structure of (1) signal transduction proteins involved in inflammation, and (2) enzymes that degrade chemotherapeutic agents.
1. Chemokine-chemokine receptor (GPCR) structures
2. High throughput screening to identify small molecule agonists and antagonists of chemokines and their GPCR receptors
3. Yeast genetics to identify and quantitate chemokine-chemokine receptor interactions
4. Mechanism of receptor activation for macrophage migration inhibitory factor
5. Identification of the substrate of MIF and structure of MIF-ligand complexes
6. Study of MIF inhibitors in disease models
7. Co-crystal structures of other protein-inhibitors complexes
Coauthors
Research Interests
Education; Immune System Diseases; Inflammation; Neoplasms; Parasitic Diseases; Pharmacology; Crystallography, X-Ray; Enzymes and Coenzymes; High-Throughput Screening Assays
Selected Publications
- Engineering of the high-affinity chemokine CXCL13 to screen CXCR5 antagonists to treat cancer and autoimmune diseasesRamu M, Rosenberg E, Kartz S, Foss F, Lolis E. Engineering of the high-affinity chemokine CXCL13 to screen CXCR5 antagonists to treat cancer and autoimmune diseases Biophysical Journal 2023, 122: 474a. DOI: 10.1016/j.bpj.2022.11.2542.
- Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanismMaschietto F, Qiu T, Wang J, Shi Y, Allen B, Lisi G, Lolis E, Batista V. Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism Computational And Structural Biotechnology Journal 2023, 21: 1066-1076. PMID: 36688026, PMCID: PMC9841741, DOI: 10.1016/j.csbj.2023.01.014.
- Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2)Tilstam P, Schulte W, Holowka T, Kim B, Piecychna M, Pantouris G, Lolis E, Leng L, Bernhagen J, Bucala R. Selective Recruitment of Lethal Pro-inflammatory Macrophages in Sepsis by MIF but not D-DT (MIF-2) The Journal Of Immunology 2019, 202: 51.9-51.9. DOI: 10.4049/jimmunol.202.supp.51.9.
- Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74Pantouris G, Ho J, Shah D, Syed MA, Leng L, Bhandari V, Bucala R, Batista VS, Loria JP, Lolis E. Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74 Angewandte Chemie International Edition 2018, 57: 7116-7119. PMID: 29669180, PMCID: PMC6282165, DOI: 10.1002/anie.201803191.
- Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74Pantouris G, Ho J, Shah D, Syed M, Leng L, Bhandari V, Bucala R, Batista V, Loria J, Lolis E. Nanosecond Dynamics Regulate the MIF‐Induced Activity of CD74 Angewandte Chemie 2018, 130: 7234-7237. DOI: 10.1002/ange.201803191.
- Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions*Rajasekaran D, Gröning S, Schmitz C, Zierow S, Drucker N, Bakou M, Kohl K, Mertens A, Lue H, Weber C, Xiao A, Luker G, Kapurniotu A, Lolis E, Bernhagen J. Macrophage Migration Inhibitory Factor-CXCR4 Receptor Interactions* Journal Of Biological Chemistry 2016, 291: 15881-15895. PMID: 27226569, PMCID: PMC4957068, DOI: 10.1074/jbc.m116.717751.
- Structural BiologyHodsdon M, Lolis E. Structural Biology 2015, 1-4. DOI: 10.1007/978-3-642-27841-9_5540-2.
- Characterization of PC2 Cterm Calcium-Binding Interaction and its Structural ImplicationsYang Y, Keeler C, Kuo I, Lolis E, Hodsdon M, Ehrlich B. Characterization of PC2 Cterm Calcium-Binding Interaction and its Structural Implications Biophysical Journal 2015, 108: 215a. DOI: 10.1016/j.bpj.2014.11.1186.
- Structural BiologyHodsdon M, Lolis E. Structural Biology 2015, 4384-4387. DOI: 10.1007/978-3-662-46875-3_5540.
- Structural Studies of Small Molecule Inhibitors of MIFCho Y, Lolis E. Structural Studies of Small Molecule Inhibitors of MIF 2012, 101-118. DOI: 10.1142/9789814335362_0005.
- Structural BiologyHodsdon M, Lolis E. Structural Biology 2011, 3549-3551. DOI: 10.1007/978-3-642-16483-5_5540.
- AV411 (Ibudilast) and AV1013 are non-competitive inhibitors of macrophage migration inhibitory factor: a novel induced-fit allosteric inhibition mechanism (133.11)Cho Y, Crichlow G, Vermeire J, Leng L, Du X, Hodsdon M, Bucala R, Cappello M, Gross M, Gaeta F, Johnson K, Lolis E. AV411 (Ibudilast) and AV1013 are non-competitive inhibitors of macrophage migration inhibitory factor: a novel induced-fit allosteric inhibition mechanism (133.11) The Journal Of Immunology 2010, 184: 133.11-133.11. DOI: 10.4049/jimmunol.184.supp.133.11.
- Structural BiologyHodsdon M, Lolis E. Structural Biology 2009, 2849-2851. DOI: 10.1007/978-3-540-47648-1_5540.
- Structural Studies of MIFLolis E, Crichlow G. Structural Studies of MIF 2007, 51-63. DOI: 10.1142/9789812775917_0004.
- The Structural Biology of ChemokinesLolis E, Murphy J. The Structural Biology of Chemokines 2007, 9-30. DOI: 10.1007/978-1-59745-020-1_2.
- Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discoveryLolis E. Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery Current Opinion In Pharmacology 2001, 1: 662-668. PMID: 11757824, DOI: 10.1016/s1471-4892(01)00112-6.
- Development of chronic colitis is dependent on the cytokine MIFde Jong Y, Abadia-Molina A, Satoskar A, Clarke K, Rietdijk S, Faubion W, Mizoguchi E, Metz C, Sahli M, ten Hove T, Keates A, Lubetsky J, Farrell R, Michetti P, van Deventer S, Lolis E, David J, Bhan A, Terhorst C. Development of chronic colitis is dependent on the cytokine MIF Nature Immunology 2001, 2: 1061-1066. PMID: 11668338, DOI: 10.1038/ni720.
- CCR2 and CCR5 receptor‐binding properties of herpesvirus‐8 vMIP‐II based on sequence analysis and its solution structureShao W, Fernandez E, Sachpatzidis A, Wilken J, Thompson D, Schweitzer B, Lolis E. CCR2 and CCR5 receptor‐binding properties of herpesvirus‐8 vMIP‐II based on sequence analysis and its solution structure The FEBS Journal 2001, 268: 2948-2959. PMID: 11358512, DOI: 10.1046/j.1432-1327.2001.02184.x.
- Comparison of the Structure of vMIP-II with Eotaxin-1, RANTES, and MCP-3 Suggests a Unique Mechanism for CCR3 Activation † , ‡Fernandez E, Wilken J, Thompson D, Peiper S, Lolis E. Comparison of the Structure of vMIP-II with Eotaxin-1, RANTES, and MCP-3 Suggests a Unique Mechanism for CCR3 Activation † , ‡ Biochemistry 2000, 39: 12837-12844. PMID: 11041848, DOI: 10.1021/bi001166f.
- Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes.Sharron M, Pöhlmann S, Price K, Lolis E, Tsang M, Kirchhoff F, Doms R, Lee B. Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes. Blood 2000, 96: 41-9. PMID: 10891428, DOI: 10.1182/blood.v96.1.41.013k53_41_49.
- Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytesSharron M, Pöhlmann S, Price K, Lolis E, Tsang M, Kirchhoff F, Doms R, Lee B. Expression and coreceptor activity of STRL33/Bonzo on primary peripheral blood lymphocytes Blood 2000, 96: 41-49. DOI: 10.1182/blood.v96.1.41.
- A cryocooling technique for protein crystals grown by dialysis from volatile solventsFernandez E, Joachimiak A, Lolis E. A cryocooling technique for protein crystals grown by dialysis from volatile solvents Journal Of Applied Crystallography 2000, 33: 168-171. DOI: 10.1107/s0021889899012406.
- Crystallographic Studies of Phosphonate-Based α-Reaction Transition-State Analogues Complexed to Tryptophan Synthase † , ‡Sachpatzidis A, Dealwis C, Lubetsky J, Liang P, Anderson K, Lolis E. Crystallographic Studies of Phosphonate-Based α-Reaction Transition-State Analogues Complexed to Tryptophan Synthase † , ‡ Biochemistry 1999, 38: 12665-12674. PMID: 10504236, DOI: 10.1021/bi9907734.
- Pro-1 of Macrophage Migration Inhibitory Factor Functions as a Catalytic Base in the Phenylpyruvate Tautomerase Activity † , ‡Lubetsky J, Swope M, Dealwis C, Blake P, Lolis E. Pro-1 of Macrophage Migration Inhibitory Factor Functions as a Catalytic Base in the Phenylpyruvate Tautomerase Activity † , ‡ Biochemistry 1999, 38: 7346-7354. PMID: 10353846, DOI: 10.1021/bi990306m.
- Macrophage migration inhibitory factor: Cytokine, hormone, or enzyme?Swope M, Lolis E. Macrophage migration inhibitory factor: Cytokine, hormone, or enzyme? 1999, 139: 1-32. PMID: 10453691, DOI: 10.1007/bfb0033647.
- Accessibility of selenomethionine proteins by total chemical synthesis: structural studies of human herpesvirus‐8 MIP‐IIShao W, Fernandez E, Wilken J, Thompson D, Siani M, West J, Lolis E, Schweitzer B. Accessibility of selenomethionine proteins by total chemical synthesis: structural studies of human herpesvirus‐8 MIP‐II FEBS Letters 1998, 441: 77-82. PMID: 9877169, DOI: 10.1016/s0014-5793(98)01520-8.
- Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factorSwope M, Sun H, Blake P, Lolis E. Direct link between cytokine activity and a catalytic site for macrophage migration inhibitory factor The EMBO Journal 1998, 17: 3534-3541. PMID: 9649424, PMCID: PMC1170690, DOI: 10.1093/emboj/17.13.3534.
- Crystal structure of chemically synthesized [N33A] stromal cell-derived factor 1α, a potent ligand for the HIV-1 “fusin” coreceptorDealwis C, Fernandez E, Thompson D, Simon R, Siani M, Lolis E. Crystal structure of chemically synthesized [N33A] stromal cell-derived factor 1α, a potent ligand for the HIV-1 “fusin” coreceptor Proceedings Of The National Academy Of Sciences Of The United States Of America 1998, 95: 6941-6946. PMID: 9618518, PMCID: PMC22694, DOI: 10.1073/pnas.95.12.6941.
- Macrophage Migration Inhibitory Factor Interactions with Glutathione and S -Hexylglutathione*Swope M, Sun H, Klockow B, Blake P, Lolis E. Macrophage Migration Inhibitory Factor Interactions with Glutathione and S -Hexylglutathione* Journal Of Biological Chemistry 1998, 273: 14877-14884. PMID: 9614090, DOI: 10.1074/jbc.273.24.14877.
- Solution Structure of Murine Macrophage Inflammatory Protein-2 † , ‡Shao W, Jerva L, West J, Lolis E, Schweitzer B. Solution Structure of Murine Macrophage Inflammatory Protein-2 † , ‡ Biochemistry 1998, 37: 8303-8313. PMID: 9622482, DOI: 10.1021/bi980112r.
- Functional and receptor binding characterization of recombinant murine macrophage inflammatory protein 2: Sequence analysis and mutagenesis identify receptor binding epitopesJerva L, Lolis E, Sullivan G. Functional and receptor binding characterization of recombinant murine macrophage inflammatory protein 2: Sequence analysis and mutagenesis identify receptor binding epitopes Protein Science 1997, 6: 1643-1652. PMID: 9260277, PMCID: PMC2143775, DOI: 10.1002/pro.5560060805.
- The subunit structure of human macrophage migration inhibitory factor: evidence for a trimerSun H, Swope M, Craig C, Bedarkar S, Bernhagen J, Bucala R, Lolis E. The subunit structure of human macrophage migration inhibitory factor: evidence for a trimer Protein Engineering Design And Selection 1996, 9: 631-635. PMID: 8875640, DOI: 10.1093/protein/9.8.631.
- Structure-Function Studies of Murine MIP-2, the Homologue of Melanoma Growth Stimulating Activity/gro-α and IL-8Lolis E, Jerva L. Structure-Function Studies of Murine MIP-2, the Homologue of Melanoma Growth Stimulating Activity/gro-α and IL-8 1996, 183-194. DOI: 10.1007/978-3-642-61180-3_17.
- Model studies of the maillard reaction of Arg-Lys with D-riboseAl-Abed Y, Ulrich P, Kapurniotu A, Lolis E, Bucala R. Model studies of the maillard reaction of Arg-Lys with D-ribose Bioorganic & Medicinal Chemistry Letters 1995, 5: 2929-2930. DOI: 10.1016/0960-894x(95)00513-s.
- Salvaging recombinants from low-efficiency ligase reactions for more efficient subcloning.Sun H, Lolis E. Salvaging recombinants from low-efficiency ligase reactions for more efficient subcloning. BioTechniques 1995, 18: 644-6, 648, 650. PMID: 7598899.
- Crystal structure of the K12M/G15A triosephosphate isomerase double mutant and electrostatic analysis of the active site.Joseph-McCarthy D, Lolis E, Komives E, Petsko G. Crystal structure of the K12M/G15A triosephosphate isomerase double mutant and electrostatic analysis of the active site. Biochemistry 1994, 33: 2815-23. PMID: 8130194, DOI: 10.1021/bi00176a010.
- Preliminary crystallographic analysis of murine macrophage inflammatory protein 2Lolis E, Sweet R, Cousens L, Tekamp-Olson P, Sherry B, Cerami A. Preliminary crystallographic analysis of murine macrophage inflammatory protein 2 Journal Of Molecular Biology 1992, 225: 913-915. PMID: 1602491, DOI: 10.1016/0022-2836(92)90411-c.
- Electrophilic catalysis in triosephosphate isomerase: the role of histidine-95.Komives E, Chang L, Lolis E, Tilton R, Petsko G, Knowles J. Electrophilic catalysis in triosephosphate isomerase: the role of histidine-95. Biochemistry 1991, 30: 3011-9. PMID: 2007138, DOI: 10.1021/bi00226a005.
- Structure of yeast triosephosphate isomerase at 1.9-A resolution.Lolis E, Alber T, Davenport R, Rose D, Hartman F, Petsko G. Structure of yeast triosephosphate isomerase at 1.9-A resolution. Biochemistry 1990, 29: 6609-18. PMID: 2204417, DOI: 10.1021/bi00480a009.
- Crystallographic analysis of the complex between triosephosphate isomerase and 2-phosphoglycolate at 2.5-A resolution: implications for catalysis.Lolis E, Petsko G. Crystallographic analysis of the complex between triosephosphate isomerase and 2-phosphoglycolate at 2.5-A resolution: implications for catalysis. Biochemistry 1990, 29: 6619-25. PMID: 2204418, DOI: 10.1021/bi00480a010.
- Transition-State Analogues in Protein Crystallography: Probes of the Structural Source of Enzyme CatalysisLolis E, Petsko G. Transition-State Analogues in Protein Crystallography: Probes of the Structural Source of Enzyme Catalysis Annual Review Of Biochemistry 1990, 59: 597-630. PMID: 2197984, DOI: 10.1146/annurev.bi.59.070190.003121.
- Crystallography and site-directed mutagenesis of yeast triosephosphate isomerase: what can we learn about catalysis from a "simple" enzyme?Alber T, Davenport R, Giammona D, Lolis E, Petsko G, Ringe D. Crystallography and site-directed mutagenesis of yeast triosephosphate isomerase: what can we learn about catalysis from a "simple" enzyme? Cold Spring Harbor Symposia On Quantitative Biology 1987, 52: 603-13. PMID: 3331346, DOI: 10.1101/sqb.1987.052.01.069.
- Chiral discrimination in the covalent binding of bis(phenanthroline)dichlororuthenium(II) to B-DNABarton J, Lolis E. Chiral discrimination in the covalent binding of bis(phenanthroline)dichlororuthenium(II) to B-DNA Journal Of The American Chemical Society 1985, 107: 708-709. DOI: 10.1021/ja00289a035.