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School of Medicine
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We are interested in studying molecular abnormalities that underlie diseases to design targeted molecular therapies. Alterations in the regulation and protein:protein interaction due to mutations are implicated from cardiovascular disease to cancer. Understanding the structural and mechanistic details of each signaling event and the protein-protein interactions involved is our key to design the next generation of targeted therapies. We use techniques from biophysics with an emphasis in structural biology: biochemistry, cell-based assay, X-ray crystallography, SAXS, ITC, SPR, to test the proof of principle of therapies.
Regulation of Voltage gated channels
Voltage-gated sodium channels are responsible for the action potential in excitable cells such as neuron, cardiac and skeletal muscle. We are studying the structural basis of channelopathic mutations that give rise to electrical disturbances known as arrhythmias and myotonias. Exploring the effect of the channel mutations and the corresponding protein:protein interaction we are designing mechanistically- coherent therapies such as compensatory mutants for Brugada and long QT syndromes
For example, Calmodulin binds the C-terminal tail of sodium and calcium voltage-gated channels, we are probing whether Brugada and long QT syndrome’ mutations reduce affinity, dislodge the binding partner using a integrated approach from electrophysiology to structural biology in state-of-the-art models such as culture myocytes, transgenic mice and myocytes derived from human iPSC cells.
Our goal is to design precision cancer therapies that target wild type and mutant PI3Kα, the lipid kinase that controls blood sugar levels via insulin, new blood vessel formation, and how cells grow and move. Mutations in PI3Kα are present in about 20% of the cancers and result in unregulated cell growth and tumor progression. We seek to understand the structural differences between wild-type and oncogenic mutant PI3Kα to discover small molecules that bind to novel binding sites, rather than canonical ATP-competitive inhibitors. A detailed understanding of these key differences will provide an opportunity to discover novel drugs that target previously unexplored binding sites on the protein that are able to selectively “switch off” the mutant protein, leaving the wild-type protein, and thus its normal cellular functions, untouched.
Gabelli Lab Members
- Sandra Gabelli, Ph.D.
- Sweta Maheshwari, Ph.D.
- Michelle Miller, Ph.D
- Puchong Thirawatanond, Bs
Targeting PI3Ka Mutants for Precision Therapeutics
- BC151831 Department of Defense – CDMRP
- Role: PI
Calmodulin regulation of Na channels: from function and function to disease.
- 1 R01 HL128743-01A1
- Role: co-Investigator
- Multi-PI (Tomaselli is Lead PI)
Nucleolus: a novel paradigm for PARP1/PARP2 functions and clinical application
- Allegheny Health Network-JH Cancer Res Fund
- Role: Co-PI (with Laiho, Franco, Leung
Designing anticancer PI3K inhibitors on a novel routeCompleted Projects
- Identification number: not applicable
- Margaret and Alexander Stewart Trust
- Role: PI
1. Gabelli SB, Bianchet MA, Bessman MJ, Amzel LM. The structure of ADP-ribose pyrophosphatase reveals the structural basis for the versatility of the Nudix family. Nat Struct Biol 2001 May;8(5):467-72. PMID: 11323725.
2. Gabelli SB, Bianchet MA, Ohnishi Y, Ichikawa Y, Bessman MJ, Amzel LM. Mechanism of the E.coli ADP-ribose pyrophosphatase: A Nudix Hydrolase. Biochemistry 2002. Jul 30; 41 (30):9279-85. PMID: 12135348.
3. Cho H, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ. Structure of the Extracellular region of HER2 Both Alone and in Complex with the Herceptin Fab. Nature. 2003 Feb 13;421(6924):756-60. PMID: 12610629.
4. Kang LW, Gabelli SB, Bianchet MA, Xu, WL, Bessman, MJ, Amzel, LM. The structure of a Coenzyme A pyrophosphatase from Deinococcus Radiodurans: a member of the Nudix family. J Bacteriol. 2003 Jul;185(14):4110-8. PubMed PMID: 12837785; PubMed Central PMCID: PMC164880.
5. Kang LW, Gabelli SB, Cunningham, JE, O'Handley, SF, Amzel, LM. Structure and mechanism of MT-ADPRase, a Nudix hydrolase from Mycobacterium tuberculosis. Structure. 2003. Aug:11(8):1015-23. PMID: 12906832.
6. Gabelli SB, Bianchet MA, Azurmendi HF, Xia Z., Sarawat V., Mildvan, AS. , Amzel, LM. Structure and mechanism of GDP-mannose glycosyl hydrolase: a Nudix enzyme that cleaves at carbon instead of at phosphourus. Structure. 2004. Jun;12(6):927-35. PMID: 15274914.
7. Mildvan AS, Xia Z, Azurmendi HF, Saraswat V, Massiah MA, Gabelli SB, Bianchet, Kang LW, Amzel LM. Structure and Mechanism of Nudix Hydrolases. Arch Biochem Biophys. 2005 Jan 1;433(1):129-43. PMID: 15581572.
8. Xia Z, Azurmendi HF, Lairson LL, Withers SG, Gabelli SB, Bianchet MA, Amzel LM. Mildvan AS. Mutational, Structural, and kinetic evidence for a dissociative mechanism in the GDP-mannose mannosyl hydrolase reaction. Biochemistry 2005. Jun 28:44(24) 8989-8997. PMID: 15966723.
9. Coblitz B, Shikano S, Wu M, Gabelli SB, Cockrell LM, Hanyu Y, Fu H, Amzel LM, Li M. Carboxyl-terminal recognition by 14-3-3 proteins for surface expression of membrane receptors. J Biol Chem. 2005 Oct 28;280(43):36263-72 . PMID: 16123035.
10. Nadella, M, Bianchet MA, Gabelli SB, Amzel LM. Structure and Activity of the Axon Guidance Protein MICAL. Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16830-5. Epub 2005 Nov 7. PMID: 16275926; PMCID: PMC1277968.
*indicates senior and corresponding author. Mentees are indicated by underlining their names
1. Duong-Ly KC, Gabelli SB*. Explanatory chapter: troubleshooting protein expression: what to do when the protein is not soluble. Methods Enzymol. 2014;541:231-47. doi: 10.1016/B978-0-12-420119-4.00018-5. PubMed PMID: 24674075.
2. Duong-Ly KC, Gabelli SB*. Explanatory chapter: troubleshooting recombinant protein expression: general. Methods Enzymol. 2014;541:209-29. doi: 10.1016/B978-0-12-420119-4.00017-3. PubMed PMID: 24674074.
3. Duong-Ly KC, Gabelli SB*. Gel filtration chromatography (size exclusion chromatography) of proteins. Methods Enzymol. 2014;541:105-14. doi: 10.1016/B978-0-12-420119-4.00009-4. PubMed PMID: 24674066.
4. Duong-Ly KC, Gabelli SB*. Using ion exchange chromatography to purify a recombinantly expressed protein. Methods Enzymol. 2014;541:95-103. doi: 10.1016/B978-0-12-420119-4.00008-2. PubMed PMID: 24674065.
5. Duong-Ly KC, Gabelli SB*. Salting out of proteins using ammonium sulfate precipitation. Methods Enzymol. 2014;541:85-94. doi: 10.1016/B978-0-12-420119-4.00007-0. PubMed PMID: 24674064.
6. Duong-Ly KC, Gabelli SB*. Affinity Purification of a Recombinant Protein Expressed as a Fusion with the Maltose-Binding Protein (MBP) Tag. Methods Enzymol. 2015;559:17-26. doi: 10.1016/ bs.mie. 2014.11.004. Epub 2015 Apr 15.