Structural Genomics Consortium
The Structural Genomics Consortium (SGC) is a not-for-profit organization formed in 2004 to determine the three-dimensional structures of proteins of medical relevance, and place them in the Protein Data Bank without restriction on use. The SGC operates out of the Universities of Oxford and Toronto. Over the past five years, the SGC has accounted for ~25% of the global output of novel human protein structures each year, and ~40% of the annual global output of structures of proteins from human parasites. The SGC target proteins have relevance to human health and disease, such as diabetes, cancer and infectious diseases such as malaria.
The SGC is an 'open data' partnership. All research results are published with no restriction. The SGC is also spearheading an "open access" chemistry partnership – a new model for pre-competitive drug discovery in which the public and private sectors collaborate to generate potent and selective pharmacological inhibitors of human proteins that regulate epigenetic signalling, and commit to make these reagents available without restriction on use.
In 2011, the SGC launched a project to create high-quality recombinant antibodies to proteins implicated in epigenetic events in an effort to stimulate research on these proteins. The project is carried out in partnership with leading academic research groups in the field (Tony Kossiakoff and Shohei Koide at University of Chicago, Sachdev Sidhu at the University of Toronto) and the laboratory of Jack Greenblatt at the University of Toronto. These reagents will be made available without restriction on use.
- This section is in a list format that may be better presented using prose. (November 2017)
- "Discovery of a Selective, Substrate Competitive Inhibitor of the Lysine Methyltransferase SETD8"
- To date, SETD8 is the only methyltransferase that induces monomethylation of histone H4 lysine 20 (H4K20), which is involved with the regulation of biological processes such as DNA damage response. SETD8 also monomethylates proliferating cell nuclear antigen (PCNA) and promotes carcinogenesis, but inhibitors are virtually unknown besides nahuoic acid A. In result of this study, the first substrate-competitive inhibitor was found (UNC0379).
- "Copper is required for oncogenic BRAF signalling and tumorigenesis"
- When the BRAF kinase is mutated, it induces an active state of cancer (e.g. melanomas, thyroid cancer, etc.). The study found that when Copper Transporter 1 (CTR1) levels are decreased, the BRAF-related signaling and tumorigenesis levels decrease, also. Next, when human cells are transformed by BRAF or resistant to its inhibition, copper chelators used to treat Wilson's disease can help lessen tumor growth. When combined, the results of this study indicate that copper chelation therapy could be a very strong candidate for treating cancers related to any BRAF mutation.
- "LRIG2 mutations cause urofacial syndrome"
- Urofacial syndrome (UFS) is linked with a major risk of kidney failure and unique facial expression when crying, smiling, or laughing. Those afflicted with UFS have a mutated LRIG2, which is a protein that is heavily involved with tumorigenesis and neural cell signaling. Previous studies showed that UFS can also be caused by mutations in encoding heparanase-2 (HPSE2), and after studying nerve fascicles within muscle bundles in the human fetal bladder, it is confirmed that both are involved in the neural development of the urinary tract.
- "Human-Chromatin-Related Protein Interactions Identify a Demethylase Complex Required for Chromosome Segregation"
- The study resulted in a comprehensive protein-protein interaction map (chromatin-related) while also identifying 164 chromatin-modifying complexes. Also, they found that KDM8 and RCCD1 form a histone demethylase complex, which plays a very big role in the chromosome's stability and division.
- "Protein Interferon-Stimulated Gene 15 Conjugation Delays but Does Not Overcome Coronavirus Proliferation in a Model of Fulminant Hepatitis"
- The study revolved around the pathway in the human immune system dealing with a coronavirus diagnosis. The results had a great indication of the ISG15 pathway being of great significance. Though there are likely numerous pathways or targets, the study provided great insight into the subject, nonetheless.
- "Novel Approaches for Targeting Kinases
- Allosteric Inhibition, Allosteric Activation and Pseudokinases": Deregulation of protein kinases are very involved with a plethora of different diseases, and the study involved the finding of kinase inhibitors that have good pharmacokinetic/pharmacodynamic properties. It went over the different pathways involved and the possibilities for the future medical properties.
- "The Roles of Jumonji-Type Oxygenases in Human Disease"
- The publication went over the human Jmj-type enzymes' involvement with diseases dealing with development, metabolism, and cancer. It went over the important biological processes and pathways that are heavily affected by any altering of the characteristic functions of the Jmj-type enzyme class.
- "Structural Basis for Histone Mimicry and Hijacking of Host Proteins by Influenza Virus Protein NS1"
- Diseases can arise from pathogens that mimic host proteins. The NS1 protein that is involved with influenza A that is well known for using mimicry to compete with host proteins. The study concluded that the mimicry was imperfect in its copying, but it still must have underlying involvement with influenza A.
- "Mutant Prolactin Receptor and Familial Hyperprolactinemia"
- The study dealt with three sisters with hyperprolactinemia and how their heredity is involved. The study concluded that the mutations that causes this disease leads to prolactin insensitivity and in turn a germline familial hyperprolactinemia.
- "Why is Epigenetics Important in Understanding the Pathogenesis of Inflammatory Musculoskeletal Diseases?"
- The publication went over the underlying effects epigenetics has on the pathogenesis of musculoskeletal diseases. It mostly went over how the epigenetic machinery is extremely important in homeostasis and natural development. The overview went over the therapeutic medicine relevant to rheumatoid arthritis and its development. The researchers extend this claim by saying there are epigenetic implications with other autoimmune diseases and cancer.
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- Since 2008, SGC has developed selective and cell-permeable inhibitors of protein function (chemical probes) involved in epigenetic control such as G9a methyltransferase and Lysine demethylase
- Donated more than 1500 high-resolution structures of proteins that were relevant to human medicine to online databases
- Solved the structure of the first human ABC transporter called the mitochondrial ABC transporter ABCB10
- Released 63 human protein kinases to the public domain that never had been released before publicly
The SGC has numerous notable partners, such as AbbVie, Bayer HealthCare Pharmaceuticals, and Pfizer. Recently, these organizations together have committed more than US$65 million to the consortium to sustain operation from 2011 to 2015.
Highlight publications (2008–2012)
- Vedadi, Masoud; Barsyte-Lovejoy, Dalia; Liu, Feng; Rival-Gervier, Sylvie; Allali-Hassani, Abdellah; Labrie, Viviane; Wigle, Tim J; Dimaggio, Peter A; et al. (2011). "A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells". Nature Chemical Biology. 7 (8): 566–74. doi:10.1038/nchembio.599. PMC 3184254. PMID 21743462.
- Colwill, Karen; Persson, Helena; Jarvik, Nicholas E; Wyrzucki, Arkadiusz; Wojcik, John; Koide, Akiko; Kossiakoff, Anthony A; Koide, Shohei; et al. (2011). "A roadmap to generate renewable protein binders to the human proteome". Nature Methods. 8 (7): 551–8. doi:10.1038/nmeth.1607. PMID 21572409.
- Filippakopoulos, Panagis; Qi, Jun; Picaud, Sarah; Shen, Yao; Smith, William B.; Fedorov, Oleg; Morse, Elizabeth M.; Keates, Tracey; et al. (2010). "Selective inhibition of BET bromodomains". Nature. 468 (7327): 1067–73. doi:10.1038/nature09504. PMC 3010259. PMID 20871596.
- Ceccarelli, Derek F.; Tang, Xiaojing; Pelletier, Benoit; Orlicky, Stephen; Xie, Weilin; Plantevin, Veronique; Neculai, Dante; Chou, Yang-Chieh; et al. (2011). "An Allosteric Inhibitor of the Human Cdc34 Ubiquitin-Conjugating Enzyme". Cell. 145 (7): 1075–87. doi:10.1016/j.cell.2011.05.039. PMID 21683433.
- Barr, Alastair J.; Ugochukwu, Emilie; Lee, Wen Hwa; King, Oliver N.F.; Filippakopoulos, Panagis; Alfano, Ivan; Savitsky, Pavel; Burgess-Brown, Nicola A.; et al. (2009). "Large-Scale Structural Analysis of the Classical Human Protein Tyrosine Phosphatome". Cell. 136 (2): 352–63. doi:10.1016/j.cell.2008.11.038. PMC 2638020. PMID 19167335.
- Avvakumov, George V.; Walker, John R.; Xue, Sheng; Li, Yanjun; Duan, Shili; Bronner, Christian; Arrowsmith, Cheryl H.; Dhe-Paganon, Sirano (2008). "Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1". Nature. 455 (7214): 822–5. doi:10.1038/nature07273. PMID 18772889.
- Filippakopoulos, Panagis; Kofler, Michael; Hantschel, Oliver; Gish, Gerald D.; Grebien, Florian; Salah, Eidarus; Neudecker, Philipp; Kay, Lewis E.; et al. (2008). "Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation". Cell. 134 (5): 793–803. doi:10.1016/j.cell.2008.07.047. PMC 2572732. PMID 18775312.
- Gräslund, Susanne; Nordlund, Pär; Weigelt, Johan; Bray, James; Gileadi, Opher; Knapp, Stefan; Oppermann, Udo; Arrowsmith, Cheryl; et al. (2008). "Protein production and purification". Nature Methods. 5 (2): 135–46. doi:10.1038/nmeth.f.202. PMC 3178102. PMID 18235434.
- Perkmann Markus, Schildt Henri (2015). "Open Data Partnerships between Firms and Universities: The Role of Boundary Organizations". Research Policy. 44: 1133–1143. doi:10.1016/j.respol.2014.12.006.
- Ma, A (Aug 2014). "Discovery of a Selective, Substrate-Competitive Inhibitor of the Lysine Methyltransferase SETD8". J Med Chem. 57 (15): 6822–6833. doi:10.1021/jm500871s. PMC 4136711. PMID 25032507.
- Brady, DC (May 2014). "Copper is required for oncogenic BRAF signalling and tumorigenesis". Nature. 509 (7501): 492–496. doi:10.1038/nature13180. PMC 4138975. PMID 24717435.
- Stuart, HM (2013). "LRIG2 mutations cause urofacial syndrome". Am J Hum Genet. 92 (2): 259–264. doi:10.1016/j.ajhg.2012.12.002. PMC 3567269. PMID 23313374.
- Edyta, Marcon (26 June 2014). "Human-Chromatin-Related Protein Interactions Identify a Demethylase Complex Required for Chromosome Segregation". Cell Reports. 8 (1): 297–310. doi:10.1016/j.celrep.2014.05.050. PMID 24981860. Retrieved 16 November 2014.
- Ma, Xue-Zhong (19 March 2014). "Protein Interferon-Stimulated Gene 15 Conjugation Delays but Does Not Overcome Coronavirus Proliferation in a Model of Fulminant Hepatitis". Journal of Virology. 88 (11): 6195–6204. doi:10.1128/jvi.03801-13. PMC 4093886. PMID 24648452. Retrieved 17 November 2014.
- Cowan-Jacob, Sandra. "Novel Approaches for Targeting Kinases: Allosteric Inhibition, Allosteric Activation and Pseudokinases". Future Science. 6 (5): 541–561. doi:10.4155/fmc.13.216. Retrieved 16 November 2014.
- Johansson, Catrine. "The Roles of Jumonji-Type Oxygenases in Human Disease". Future Medicine. 6 (1): 89–120. doi:10.2217/epi.13.79. PMC 4233403. Retrieved 16 November 2014.
- Qin, Su (21 December 2013). "Structural Basis for Histone Mimicry and Hijacking of Host Proteins by Influenza Virus Protein NS1". Nature Communications. 5 (3952). doi:10.1038/ncomms4952. PMID 24853335. Retrieved 16 November 2014.
- Newey, Paul (21 November 2013). "Mutant Prolactin Receptor and Familial Hyperprolactinemia". The New England Journal of Medicine. 369: 2012–2020. doi:10.1056/NEJMoa1307557. PMC 4209110. Retrieved 16 November 2014.
- Oppermann, Udo (3 April 2013). "Why Epigenetics Important in Understanding the Pathogenesis of Inflammatory Musculoskeletal Diseases?". Arthritis Research & Therapy. 15 (209). doi:10.1186/ar4186. Retrieved 16 November 2014.