Protein Crystal Structures
Established in 2004, the private-public University of Toronto partnership, the Structural Genomics Consortium (SGC), has deposited more than 1,300 structures into its protein database. Susanne Gräslund, Ph.D., discussed various high-throughput methods to generate these proteins within a range of expression hosts. Since 2011, the organization has also been involved in a large-scale project to generate recombinant antibodies to epigenetics proteins.
With a U.K. charity as its base, SGC relays funds from public and private donors to member labs in Toronto and Oxford, U.K. The group also maintains satellite labs worldwide. Approximately half of SGC’s members are dues-paying industrial firms. “It’s important to maintain that public-private balance,” Dr. Gräslund commented.
SGC’s core mission is to solve crystal structures of proteins relevant to human health, which explains the strong pharma/biopharma connection.
As part of its mandate, SGC has begun investigating chemical probes, mostly small molecules, that bind to protein targets. “These are not necessarily drug candidates, as the leap from binding to drug is very large,” Dr. Gräslund explained. “Rather, researchers use these molecules as starting points for drug discovery.”
The source of this molecular largesse is chemical libraries, whose access is provided by member companies. SGC also maintains academic collaborations, for example with the University of Colorado. A potential drawback to commercial partners is the unique agreement by which SGC publishes results freely and openly.
The consortium’s third charge is making monoclonal antibodies using purified proteins as antigens, and subsequently selecting synthetic recombinant antibodies using phage-display technology.
Binding is determined through in vitro assays and cell-based assays. “We do a lot of co-crystallizations as well,” Dr. Gräslund said. Most of the proteins employed in this work have already been solved, in their native unbound state, by crystallography. “Small molecules that bind sit in a specific locus, altering the protein’s conformation relative to its unbound state. Conformational changes cause shifts in thermal melt temperature.”
SGC is open to additional collaborations, both academic and corporate, and has space to host visiting scientists with common interests in proteomics. The consortium also holds formal courses in protein purification and crystallization.