Maria Pellegrini

Academic Appointments

Research Professor

Many processes in a living cell are regulated through the specific interaction between proteins. Targeting the disruption of protein-protein complexes for therapeutic purposes is considered a very attractive, albeit difficult, approach. In our research, we take advantage of information on the protein's overall fold, primary and secondary structure at the interface and flexibility to identify putative binding sites and design and test molecules that interfere with or block protein-protein interaction. We focus on peptides, peptidomimetics, and small molecular weight compounds.

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Nuclear magnetic resonance (NMR) provides the unique advantage of allowing to investigate both protein structure and dynamics and has been effectively employed as a screening technique, especially in fragment-based approaches. We complement our NMR studies with a number of biophysical and biochemical techniques for characterization of proteins and binding interactions (EPR, CD, fluorescence, etc.) and with computational tools for structural refinement and model building.

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(603) 646-8103
109 Burke, 008B Life Science Center
HB 6128
Department(s): 
Chemistry
Education: 
Ph.D. in Chemistry, University of Padova, 1996
“Laurea” degree (B. Sc.) in Chemistry, University of Padova, 1992

Selected Publications

Reinhart EF, Litt NA, Katzenell S, Pellegrini M, Yamamoto A, Ragusa MJ. A highly conserved glutamic acid in ALFY inhibits membrane binding to aid in aggregate clearance. Traffic. 2021 Jan;22(1-2):23-37. doi: 10.1111/tra.12771. Epub 2020 Dec 1. PubMed PMID: 33225481; PubMed Central PMCID: PMC7902475.

Midgett CR, Swindell RA, Pellegrini M, Jon Kull F. A disulfide constrains the ToxR periplasmic domain structure, altering its interactions with ToxS and bile-salts. Sci Rep. 2020 Jun 2;10(1):9002. doi: 10.1038/s41598-020-66050-5. PubMed PMID: 32488093; PubMed Central PMCID: PMC7265457.

Barczewski AH, Ragusa MJ, Mierke DF, Pellegrini M. Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO. J Vis Exp. 2019 Dec 28;(154). doi: 10.3791/60339. PubMed PMID: 31929506; PubMed Central PMCID: PMC7359928.

Bauer KM, Dicovitsky R, Pellegrini M, Zhaxybayeva O, Ragusa MJ. The structure of a highly-conserved picocyanobacterial protein reveals a Tudor domain with an RNA-binding function. J Biol Chem. 2019 Sep 27;294(39):14333-14344. doi: 10.1074/jbc.RA119.007938. Epub 2019 Aug 7. PubMed PMID: 31391250; PubMed Central PMCID: PMC6768636.

Barczewski AH, Ragusa MJ, Mierke DF, Pellegrini M. The IKK-binding domain of NEMO is an irregular coiled coil with a dynamic binding interface. Sci Rep. 2019 Feb 27;9(1):2950. doi: 10.1038/s41598-019-39588-2. PubMed PMID: 30814588; PubMed Central PMCID: PMC6393490.

Zhao Y, Cushing PR, Smithson DC, Pellegrini M, Pletnev AA, Al-Ayyoubi S, Grassetti AV, Gerber SA, Guy RK, Madden DR. Cysteine modifiers suggest an allosteric inhibitory site on the CAL PDZ domain. Biosci Rep. 2018 Aug 31;38(4). doi: 10.1042/BSR20180231. Print 2018 Aug 31. PubMed PMID: 29472314; PubMed Central PMCID: PMC6435542.

Xia X, Katzenell S, Reinhart EF, Bauer KM, Pellegrini M, Ragusa MJ. A pseudo-receiver domain in Atg32 is required for mitophagy. Autophagy. 2018;14(9):1620-1628. doi: 10.1080/15548627.2018.1472838. Epub 2018 Aug 1. PubMed PMID: 29909755; PubMed Central PMCID: PMC6135581.

Busatto N, Salvagnin U, Resentini F, Quaresimin S, Navazio L, Marin O, Pellegrini M, Costa F, Mierke DF, Trainotti L. The Peach RGF/GLV Signaling Peptide pCTG134 Is Involved in a Regulatory Circuit That Sustains Auxin and Ethylene Actions. Front Plant Sci. 2017;8:1711. doi: 10.3389/fpls.2017.01711. eCollection 2017. PubMed PMID: 29075273; PubMed Central PMCID: PMC5641559.

Xia X, Pellegrini M, Ragusa MJ. Backbone and side chain resonance assignments for a structured domain within Atg32. Biomol NMR Assign. 2017 Oct;11(2):211-214. doi: 10.1007/s12104-017-9750-y. Epub 2017 Aug 1. PubMed PMID: 28766175; PubMed Central PMCID: PMC5693731.

Privett BR, Pellegrini M, Kovacikova G, Taylor RK, Skorupski K, Mierke D, Kull FJ. Identification of a Small Molecule Activator for AphB, a LysR-Type Virulence Transcriptional Regulator in Vibrio cholerae. Biochemistry. 2017 Jul 25;56(29):3840-3849. doi: 10.1021/acs.biochem.7b00337. Epub 2017 Jul 11. PubMed PMID: 28640592; PubMed Central PMCID: PMC5963692.

Midgett CR, Almagro-Moreno S, Pellegrini M, Taylor RK, Skorupski K, Kull FJ. Bile salts and alkaline pH reciprocally modulate the interaction between the periplasmic domains of Vibrio cholerae ToxR and ToxS. Mol Microbiol. 2017 Jul;105(2):258-272. doi: 10.1111/mmi.13699. Epub 2017 May 17. PubMed PMID: 28464377; PubMed Central PMCID: PMC5498992.

Bucur O, Gaidos G, Yatawara A, Pennarun B, Rupasinghe C, Roux J, Andrei S, Guo B, Panaitiu A, Pellegrini M, Mierke DF, Khosravi-Far R. "A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death." Sci Rep. 2015 May 11;5:9893. doi: 10.1038/srep09893. PMID: 25962125 

http://www.ncbi.nlm.nih.gov/pubmed/25962125

Song GJ, Leslie KL, Barrick S, Mamonova T, Fitzpatrick JM, Drombosky KW, Peyser N, Wang B, Pellegrini M, Bauer PM, Friedman PA, Mierke DF, Bisello A. "Phosphorylation of Ezrin-Radixin-Moesin-binding Phosphoprotein 50 (EBP50) by Akt Promotes Stability and Mitogenic Function of S-phase Kinase-associated Protein-2 (Skp2)." J Biol Chem. 2015 290(5):2879-87.  doi: 10.1074/jbc.M114.609768. PMID: 25492869

http://www.ncbi.nlm.nih.gov/pubmed/25492869

Yatawara A, Gaidos G, Rupasinghe CN, O'Hara BA, Pellegrini M, Atwood WJ, Mierke DF. "Small-molecule inhibitors of JC polyomavirus infection." J Pept Sci. 2014 doi: 10.1002/psc.2731. PMID: 25522925

http://www.ncbi.nlm.nih.gov/pubmed/25522925

Guo B, Audu CO, Cochran JC, Mierke DF, Pellegrini M. Protein Engineering of the N-terminus of NEMO: structure stabilization and rescue of IKKβ binding. Biochemistry. 2014 53(43):6776-85. PMID: 25286246 DOI:10.1021/bi500861x

http://www.ncbi.nlm.nih.gov/pubmed/25286246

Guo B, Gurel PS, Shu R, Higgs HN, Pellegrini M, Mierke DF.Monitoring ATP hydrolysis and ATPase inhibitor screening using (1)H NMR. Chem Commun (Camb). 2014 Sep 6;50(81):12037-9. doi: 10.1039/c4cc04399e. PMID: 25170530

http://www.ncbi.nlm.nih.gov/pubmed/25170530

Fitzpatrick JM, Pellegrini M, Cushing PR, Mierke DF. Small Molecule Inhibition of the Na+/H+ Exchange Regulatory Factor 1 and Parathyroid Hormone 1 Receptor Interaction. Biochemistry. 2014 ;53(37):5916-22. PMID: 25171053

http://www.ncbi.nlm.nih.gov/pubmed/25171053

Audu CO, Plati JJ, Pellegrini M, Mierke DF. Engineering a soluble parathyroid hormone GPCR mimetic. Proteins. 2014 Jul;82(7):1370-5. doi: 10.1002/prot.24503. Epub 2014 Jan 15.

http://www.ncbi.nlm.nih.gov/pubmed/24375686

Audu, C. O.; Cochran, J. C.; Pellegrini, M.; Mierke, D. F. Recombinant Production of TEV Cleaved Human Parathyroid Hormone. (2013) Journal of Peptide Science, 19, 504–510. PMCID:PMC3755510

http://www.ncbi.nlm.nih.gov/pubmed/23794508

Pellegrini M, Willen L, Perroud M, Krushinskie D, Strauch K, Cuervo H, Day ES, Schneider P, Zheng TS.: Structure of the extracellular domains of human and xenopus Fn14: Implications in the evolution of TWEAK and Fn14 interactions. FEBS J. 2013 Apr;280(8):1818-29

http://www.ncbi.nlm.nih.gov/pubmed/23438059

Audu CO, O'Hara B, Pellegrini M, Wang L, Atwood W, Mierke DF. Reigning in Polyoma Virus associated nephropathy: design and characterization of a template mimicking BK Viral Coat Protein cellular binding. Biochemistry, 2012 51 (41): 8092-8099. NIHMS412129

http://www.ncbi.nlm.nih.gov/pubmed/23002929

Cushing PR, Vouilleme L, Pellegrini M, Boisguerin P, Madden DR. A stabilizing influence: CAL PDZ inhibition extends the half-life of F508-CFTR. Angew Chem Int Ed Engl. 2010 Dec 17;49(51):9907-11. PMCID: PMC3033200.

Lowden, MJ, Skorupski, K, Pellegrini, M, Chiorazzo, MG, Taylor, RK., and Kull, FJ. Structure of Vibrio cholerae ToxT reveals a mechanism for fatty acid regulation of virulence genes. PNAS 2010, 107:2860-65 PMCID: PMC284031.

Ahn KH, Pellegrini M, Tsomaia N, Yatawara AK, Kendall DA, Mierke DF Structural analysis of the human cannabinoid receptor one carboxyl-terminus identifies two amphipathic helices. Biopolymers. 2009 91(7):565-73. PMCID:PMC2698224

Rushe M, Silvian L , Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A. "Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site." Structure 2008 16:798-808

http://www.ncbi.nlm.nih.gov/pubmed/18462684

Baker DP, Lin EY, Lin K, Pellegrini M, Petter RC, Chen LL, Arduini RM, Brickelmaier M, Wen D, Hess DM, Chen L, Grant D, Whitty A, Gill A, Lindner DJ, Pepinsky RB. "N-terminally PEGylated human interferon-beta-1a with improved pharmacokinetic properties and in vivo efficacy in a melanoma angiogenesis model." Bioconjug. Chem. 2006 17:179-88.

Seck T, Pellegrini M, Florea AM, Grignoux V, Baron R, Mierke DF, Horne WC. "The delta e13 isoform of the calcitonin receptor forms a six-transmembrane domain receptor with dominant-negative effects on receptor surface expression and signaling." Mol. Endocrinol. 2005 19:2132-44.

Cusack KP, Arnold LD, Barberis CE, Chen H, Ericsson AM, Gaza-Bulseco GS, Gordon TD, Grinnell CM, Harsch A, Pellegrini M, Tarcsa E. "A 13C NMR approach to categorizing potential limitations of alpha,beta-unsaturated carbonyl systems in drug-like molecules." Bioorg. Med. Chem. Lett. 2004 14:5503-7.

Pellegrini M, Bremer AA, Ulfers AL, Boyd ND, Mierke DF. "Molecular characterization of the substance P/neurokinin-1 receptor complex: development of an experimentally based model." J. Biol. Chem. 2001 276:22862-7 .

Pellegrini M, Liehr S, Fisher AL, Laub PB, Cooperman BS, Mierke DF. "Structure-based optimization of peptide inhibitors of mammalian ribonucleotide reductase." Biochemistry 2000 39:12210-5.

Pellegrini M, Mierke DF. "Molecular complex of cholecystokinin-8 and N-terminus of the cholecystokinin A receptor by NMR spectroscopy." Biochemistry 1999 38:14775-83.

Pellegrini M, Bisello A, Rosenblatt M, Chorev M, Mierke DF. "Binding domain of human parathyroid hormone receptor: from conformation to function." Biochemistry 1998 37:12737-43.

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Speaking engagements

NESS - North Eastern Structure Symposium 2014: Structural Biology of Inflammation
Maria Pellegrini
"Fishin' for Inhibitors of NEMO"

http://www.sb.uconn.edu/ness14.html