Dr Chrisostomos Prodromou
| Post: | Senior Research Fellow (Genome Damage and Stability) |
| Location: | Genome Centre G4.02 |
| Email: | Chris.Prodromou@sussex.ac.uk |
Telephone numbers | |
| Internal: | 8347 |
| UK: | (01273) 678347 |
| International: | +44 1273 678347 |
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Biography
Teaching Roles
Lectures
Structural Basis of Biological Function (C7114)
Tutor
Molecular Biology (C7004)
Essential Skills in Life Sciences (C7027)
Biological Chemistry (C7024)
Cell Biology (C7141)
Academic Advisor
Biomedical Science
Life Sceince Final Year Reaseach Project (C7127)
Academic positions
2010-Present, Senior Research Fellow, University of Sussex
1999-2010, Senior Staff Scientist, Institute of Cancer Research, London
1991-1999, Research Fellow, University College London
1988-1991 Research Assistantship, University College London
Relevant qualifications
1988 PhD Molecular Genetics, Queen Mary College, University of London
Role
Senior Research Fellow
Community and Business
Domainex is a drug discovery organization committed to excellence; providing high quality efficient drug target production, virtual hit finding, assay development, medicinal chemistry and computational chemistry services, to pharmaceutical, biotech and academic organizations, as well as developing its own pipeline of novel oncology drugs.
Research and areas of interest
My interests over the past 20 years have been directed towards understanding molecular chaperones and how they achieve folding and maturation of proteins. I have particularly concentrated on the Hsp90 chaperone complex. My aims are to understand the molecular details by which Hsp90, and indeed Hsp70, which also plays a role in some Hsp90 complexes, brings about the maturation of proteins (known as client proteins). I have used biochemical, genetic and structural approaches to gain an insight into Hsp90 mechanistic action and regulation of its chaperone cycle. The activation of client proteins by Hsp90 is also dependent on a number of co-chaperones that aid/regulate Hsp90 and its chaperone cycle, to achieve maturation of client proteins. These include Cdc37, Hop/Sti1, Sba1/p23, Aha1, PP5, Xap2, Unc-45, Cyp40, Rar1, Sgt1, FKBP51 and FKBP52 amongst others. My aims are to understand how Hsp90 and such co-chaperones co-operate to bring about the maturation of client proteins.
As Hsp90 is essential for the maturation of a variety of oncogenes my research has been directed towards structure-based drug design against the N-terminal ATP-binding domain of Hsp90. I am also currently collaborating in the development of C-terminal binding inhibitors of Hsp90.
Another aspect of my research involves determining the resistance mechanisms of Hsp90 targeted drugs. I have determined the natural resistance mechanism for radicicol, a macrocyclic antifungal antibiotic, a drug that targets the N-terminal ATP-binding site of Hsp90. I am currently determining the resistance mechanism against another class of Hsp90 inhibitors known as ansamysin antibiotics that include geldanamycin, macbecin and 17-AAG that also target the same N-terminal site.
I have also been active in determining the interaction of co-chaperones that are part of the innate immune system, with Hsp90 and trying to understand the molecular basis by which innate immune complexes help to protect cells from disease.
Recently my interests have turned to Sacsin. I have identified that it possesses homology to the N-terminal and middle domains of Hsp90 (unpublished data). Mutations in Sacsin cause of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). ARSACS is an early onset neurodegenerative disease with high prevalence in the Charlevoix-Saguenay-Lac-Saint-Jean region of Quebec. It is characterized by absent sensory-nerve conduction, reduced motor-nerve velocity and hypermyelination of retinal-nerve fibers. My aim is to understand how sacsin and Hsp90 are structural related and how they are mechanistically related or otherwise.
Proteins in Action
Structural Basis of Biological Function (C7114)
Tutor
Molecular Biology (C7004)
Essential Skills in Life Sciences (C7027)
Biologuical Chemistry (C7024)
Cell Biology (C7141)
Academic Advisor
Biomedical Science
Life Sceince Final Year Reaseach Project (C7127)
Student Consultation
My ofice hours are 9 to 5.30 pm. Please email me (chris.prodromou@sussex.ac.uk) should you require to discuss any issues so that we can arrange a mutual time to meet.
Kitson, Russell R A, Chang, Chuan-Hsin, Xiong, Rui, Williams, Huw E L, Davis, Adrienne L, Lewis, William, Dehn, Donna L, Siegel, David, Roe, S Mark, Prodromou, Chrisostomos, Ross, David and Moody, Christopher J (2013) Synthesis of 19-substituted geldanamycins with altered conformations and their binding to heat shock protein Hsp90. Nature Chemistry, 5 (4). pp. 307-314. ISSN 1755-4330
Polier, Sigrun, Samant, Rahul S, Clarke , Paul A, Workman, Paul, Prodromou, Chrisostomos and Pearl, Laurence H (2013) ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nature Chemical Biology, 9 (5). pp. 307-312. ISSN 1552-4450
Truman, Andrew W, Kristjansdottir, Kolbrun, Wolfgeher, Donald, Hasin , Naushaba, Polier, Sigrun, Zhang, Hong, Perrett, Sarah, Prodromou, Chrisostomos, Jones, Gary W and Kron, Stephen J (2012) CDK-dependent Hsp70 phosphorylation controls G1 cyclin abundance and cell-cycle progression. Cell, 151 (6). pp. 1308-1318. ISSN 0092-8674
Xu, Wanping, Mollapour, Mehdi, Prodromou, Chrisostomos, Wang, Suiquan, Scroggins, Bradley T, Palchick, Zach, Beebe, Kristin, Siderius, Marco, Lee, Min-Jung, Couvillon , Anthony, Trepel, Jane B, Miyata, Yoshihiko, Matts, Robert and Neckers, Len (2012) Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine. Molecular Cell, 47 (3). pp. 434-443. ISSN 1097-2765
Prodromou, Chrisostomos (2012) The 'active life' of Hsp90 complexes. BBA - Molecular Cell Research, 1823 (3). pp. 614-623. ISSN 0006-3002
Tsutsumi, Shinji, Mollapour, Mehdi, Prodromou, Chrisostomos, Lee, Chung-Tien, Panaretou, Barry, Yoshida, Soichiro, Mayer, Matthias P and Neckers, Leonard M (2012) Charged linker sequence modulates eukaryotic heat shock protein 90 (Hsp90) chaperone activity. Proceedings of the National Academy of Sciences, 109 (8). pp. 2937-2942. ISSN 1091-6490
Sharp, Swee Y, Roe, S Mark, Kazlauskas, Egidijus, Čikotienė, Inga, Workman, Paul, Matulis, Daumantas and Prodromou, Chrisostomos (2012) Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors. PLoS Genetics, 7(9) (e44642). ISSN 1553-7390
Day, James E H, Sharp, Swee Y, Rowlands, Martin G, Aherne, Wynne, Hayes, Angela, Raynaud, Florence I, Lewis, William, Roe, S Mark, Prodromou, Chrisostomos, Pearl, Laurence H, Workman, Paul and Moody, Christopher J (2011) Targeting the Hsp90 Molecular Chaperone with Novel Macrolactams. Synthesis, Structural, Binding, and Cellular Studies. ACS Chemical Biology, 6 (12). pp. 1339-1347. ISSN 1554-8929
Millson, Stefan H, Chua, Chun-Song, Roe, S Mark, Polier, Sigrun, Solovieva, Svetlana, Pearl, Laurence H, Sim, Tiow-Suan, Prodromou, Chrisostomos and Piper, Peter W (2011) Features of the Streptomyces hygroscopicus HtpG reveal how partial geldanamycin resistance can arise with mutation to the ATP binding pocket of a eukaryotic Hsp90. FASEB Journal, 25 (11). pp. 3828-3837. ISSN 0892-6638
Mollapour, Mehdi, Tsutsumi, Shinji, Truman, Andrew W, Xu, Wanping, Vaughan, Cara K, Beebe, Kristin, Konstantinova, Anna, Vourganti, Srinivas, Panaretou, Barry, Piper, Peter W, Trepel, Jane B, Prodromou, Chrisostomos, Pearl, Laurence H and Neckers, Len (2011) Threonine 22 Phosphorylation Attenuates Hsp90 Interaction with Cochaperones and Affects Its Chaperone Activity. Molecular Cell, 41 (6). pp. 672-681. ISSN 1097-2765
Maclagan, Kate, Tommasi, Rita, Laurine, Emmanuelle, Prodromou, Chrisostomos, Driscoll, Paul C, Pearl, Laurence H, Reich, Stefanie and Savva, Renos (2011) A combinatorial method to enable detailed investigation of protein-protein interactions. Future Medicinal Chemistry, 3 (3). pp. 271-282. ISSN 1756-8919
Day, James E H, Sharp, Swee Y, Rowlands, Martin G, Aherne, Wynne, Lewis, William, Roe, S Mark, Prodromou, Chrisostomos, Pearl, Laurence H, Workman, Paul and Moody, Christopher J (2010) Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies. Chemistry - A European Journal, 16 (34). pp. 10366-10372. ISSN 0947-6539
Zhang, Minghao, Kadota, Yasuhiro, Prodromou, Chrisostomos, Shirasu, Ken and Pearl, Laurence H (2010) Structural basis for assembly of Hsp90-Sgt1-CHORD protein complexes: implications for chaperoning of NLR innate immunity receptors. Molecular Cell, 39 (2). pp. 269-281. ISSN 1097-2765
Millson, Stefan H., Prodromou, Chrisostomos and Piper, Peter W. (2010) A simple yeast-based system for analyzing inhibitor resistance in the human cancer drug targets Hsp90alpha/beta. Biochemical Pharmacology, 79 (11). pp. 1581-1588. ISSN 0006-2952
Mollapour, Mehdi, Tsutsumi, Shinji, Donnelly, Alison C, Beebe, Kristin, Tokita, Mari J, Lee, Min-Jung, Lee, Sunmin, Morra, Giulia, Bourboulia, Dimitra, Scroggins, Bradley T, Colombo, Giorgio, Blagg, Brian S, Panaretou, Barry, Stetler-Stevenson, William G, Trepel, Jane B, Piper, Peter W, Prodromou, Chrisostomos, Pearl, Laurence H and Neckers, Len (2010) Swe1(Wee1)-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function. Molecular Cell, 37 (3). pp. 333-343. ISSN 1097-2765
Rowlands, Martin, McAndrew, Craig, Prodromou, Chris, Pearl, Laurence, Kalusa, Andrew, Jones, Keith, Workman, Paul and Aherne, Wynne (2010) Detection of the ATPase Activity of the Molecular Chaperones Hsp90 and Hsp72 Using the Transcreener™ ADP Assay Kit. Journal of Biomolecular Screening, 15 (3). pp. 279-86. ISSN 1087-0571
Tsutsumi, Shinji, Mollapour, Mehdi, Graf, Christian, Lee, Chung-Tien, Scroggins, Bradley T, Xu, Wanping, Haslerova, Lenka, Hessling, Martin, Konstantinova, Anna A, Trepel, Jane B, Panaretou, Barry, Buchner, Johannes, Mayer, Matthias P, Prodromou, Chrisostomos and Neckers, Len (2009) Hsp90 charged-linker truncation reverses the functional consequences of weakened hydrophobic contacts in the N domain. Nature Structural and Molecular Biology , 16 (11). pp. 1141-1147. ISSN 1545-9993
Prodromou, Chrisostomos (2009) Strategies for Stalling Malignancy: Targeting Cancer's Addiction to Hsp90. Current Topics in Medicinal Chemistry, 9 (15). pp. 1352-1368. ISSN 1568-0266
Nilapwar, Sanjay, Williams, Eleanor, Fu, Christopher, Prodromou, Chrisostomos, Pearl, Laurence H, Williams, Mark A and Ladbury, John E (2009) Structural-Thermodynamic Relationships of Interactions in the N-Terminal ATP-Binding Domain of Hsp90. Journal of Molecular Biology, 392 (4). pp. 923-936. ISSN 0022-2836
Prodromou, Chrisostomos, Nuttall, James M, Millson, Stefan H, Roe, S Mark, Sim, Tiow-Suan, Tan, Doreen, Workman, Paul, Pearl, Laurence H and Piper, Peter W (2009) Structural basis of the radicicol resistance displayed by a fungal hsp90. ACS Chemical Biology, 4 (4). pp. 289-297. ISSN 1554-8929
Mayer, Matthias P, Prodromou, Chrisostomos and Frydman, Judith (2009) The Hsp90 mosaic: a picture emerges. Nature Structural and Molecular Biology, 16 (1). pp. 2-6. ISSN 1545-9993
Vaughan, Cara K, Piper, Peter W, Pearl, Laurence H and Prodromou, Chrisostomos (2009) A common conformationally coupled ATPase mechanism for yeast and human cytoplasmic HSP90s. FEBS Journal, 276 (1). pp. 199-209. ISSN 1742-464X
Zhang, Minghao, Botër, Marta, Li, Kuoyu, Kadota, Yasuhiro, Panaretou, Barry, Prodromou, Chrisostomos, Shirasu, Ken and Pearl, Laurence H (2008) Structural and functional coupling of Hsp90- and Sgt1-centred multi-protein complexes. EMBO Journal, 27 (20). pp. 2789-2798. ISSN 0261-4189
Vaughan, Cara K, Mollapour, Mehdi, Smith, Jennifer R, Truman, Andrew, Hu, Bin, Good, Valerie M, Panaretou, Barry, Neckers, Len, Clarke, Paul A, Workman, Paul, Piper, Peter W, Prodromou, Chrisostomos and Pearl, Laurence H (2008) Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37. Molecular Cell, 31 (6). pp. 886-895. ISSN 1097-2765
Millson, Stefan H, Vaughan, Cara K, Zhai, Chao, Ali, Maruf M U, Panaretou, Barry, Piper, Peter W, Pearl, Laurence H and Prodromou, Chrisostomos (2008) Chaperone ligand-discrimination by the TPR-domain protein Tah1. Biochemical Journal, 413. pp. 261-268. ISSN 0264-6021
Brough, Paul A., Pearl, Laurence H., Prodromou, Chrisostomos and et al, (2008) 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer. Journal of Medicinal Chemistry, 51 (2). pp. 196-218. ISSN 0022-2623
Eccles, Suzanne A, Massey, Andy, Raynaud, Florence I, Sharp, Swee Y, Box, Gary, Valenti, Melanie, Patterson, Lisa, de Haven Brandon, Alexis, Gowan, Sharon, Boxall, Frances, Aherne, Wynne, Rowlands, Martin, Hayes, Angela, Martins, Vanessa, Urban, Frederique, Boxall, Kathy, Prodromou, Chrisostomos, Pearl, Laurence, James, Karen, Matthews, Thomas P, Cheung, Kwai-Ming, Kalusa, Andrew, Jones, Keith, McDonald, Edward, Barril, Xavier, Brough, Paul A, Cansfield, Julie E, Dymock, Brian, Drysdale, Martin J, Finch, Harry, Howes, Rob, Hubbard, Roderick E, Surgenor, Alan, Webb, Paul, Wood, Mike, Wright, Lisa and Workman, Paul (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Research, 68 (8). pp. 2850-2860. ISSN 0008-5472
Martin, Christine J, Gaisser, Sabine, Challis, Iain R, Carletti, Isabelle, Wilkinson, Barrie, Gregory, Matthew, Prodromou, Chrisostomos, Roe, S Mark, Pearl, Laurence H, Boyd, Susan M and Zhang, Ming-Qiang (2008) Molecular characterization of macbecin as an Hsp90 inhibitor. Journal of Medicinal Chemistry, 51 (9). pp. 2853-2857. ISSN 0022-2623
Pearl, Laurence H, Prodromou, Chrisostomos and Workman, Paul (2008) The Hsp90 molecular chaperone: an open and shut case for treatment. Biochemical Journal, 410. pp. 439-453. ISSN 0264-6021
Hawkins, Thomas A, Haramis, Anna-Pavlina, Etard, Christelle, Prodromou, Chrisostomos, Vaughan, Cara K, Ashworth, Rachel, Ray, Saikat, Behra, Martine, Holder, Nigel, Talbot, William S, Pearl, Laurence H, Strähle, Uwe and Wilson, Stephen W (2008) The ATPase-dependent chaperoning activity of Hsp90a regulates thick filament formation and integration during skeletal muscle myofibrillogenesis. Development, 135 (6). pp. 1147-1156. ISSN 0950-1991