Website:

http://www.nesg.org/

NESG Biomedical Themes

Studies of the molecular aspects of cancer and, more broadly, human developmental biology, are a particular strength of several of the NESG home institutions, exemplified by the Cancer Institute of New Jersey (CINJ) at Rutgers, and the Ontario Cancer Institute in Toronto. For this reason, our primary biomedical theme focuses a portion of our structural genomics efforts on the analysis of protein networks related to cancer and developmental biology.

Structural genomics provides an important approach for characterizing and understanding systems biology. As a step towards better integrating 3D structural information in cancer systems biology, we have constructed a Human Cancer Pathway Interaction Network (HCPIN) by analysis of several classical cancer-associated signaling pathways and their physical protein-protein interactions. At least half of HCPIN proteins are either directly associated or interact with multiple signaling pathways.

While some 45% of residues in these proteins are in proteins sequence segments that meet criteria sufficient for approximate homology modeling (Blast E_val <10-6), only 20% of residues in these proteins are structurally covered using high accuracy homology modeling criteria (i.e., at least 80% sequence identity over ~ 100 residues), or by actual experimental structures. The remaining 80% of the HCPIN proteome provides over 1100 human protein targets for large-scale structural genomics efforts. The HCPIN website provides a comprehensive description of this biomedically important network, together with experimental and homology models of HCPIN proteins useful for cancer biology research.

In order to complement and enrich cancer systems biology, we have targeted hundreds of proteins and protein domains from the HCPIN proteome for protein sample production and 3D structure determination. This network-based target selection approach provides a framework not only for completing structural coverage of a disease-associated protein interaction network, but also provides specific hypotheses regarding protein interaction partners which can be tested by co-expression, cocrystallization, and 3D structure determination of the resulting protein-protein complexes. Six NESG structures from the HCPIN have been determined and deposited in the PDB to date. The long-range goal of this effort is to provide a comprehensive 3D structure-function database for human cancer-associated proteins and their interaction network.

A second biomedical theme introduced in PSI-2 involves the structural characterization of the complete set of lipoproteins that function as membrane-anchored, but soluble, proteins in the periplasmic space of gram negative bacteria, such as E. coli, and on the membrane surface of gram positive bacteria, such as B. subtilis and B. anthrax. These secreted proteins are important in conferring antibiotic resistance. Ten NESG structures from the Biomedical Lipoprotein target set have been determined and deposited in the PDB to date.

The NESG is also targeting specific MEGA families of high potential biomedical impact including the START domain family and the Ubiquitin domain families; several structures have been determined from each of these families in PSI1 and PSI2. We are also completing structural characterization of the FeS cluster assembly BioNet, which was targeted by NESG in PSI1.