Joining Forces to Reveal Structures

Figuring out G-protein-coupled receptor (GPCR) structures is high risk. Lance Stewart, vice president of deCode Biostructures, believes that not having GPCR structures is also high risk and is costing the pharmaceutical industry much money. The industry has been successful without the structures, he acknowledges, but asks, "How many big diseases are left with unmet needs--ones where GPCR is a centerpiece in the physiology and no one has gotten any distance with chemistry and screening?"

GPCRs and ion channels are proteins in the cell membrane and thus important cellular information checkpoints. GPCRs have been implicated in a wide range of diseases and disorders, from allergies to cancer and from pain to cardiovascular dysfunction. Estimates vary, but approximately half of marketed drugs target GPCRs.

Stewart proposes establishing a risk-sharing consortium of drug companies to determine GPCR structures. Consortium members would define targets of interest and offer a share of the funding and ligands, through an auditing firm, to the organization scheduled to do the protein crystallography. The pool of ligands would be identity-protected and not accessible to individual members. But once a GPCR structure is determined, the coordinate set would be delivered to all consortium members along with the methods and protocols. Stewart has talked to a number of companies, but the project has yet to mature.

Although there's no such consortium in the U.S., John Norvell, director of the Protein Structure Initiative (PSI) sponsored by the National Institutes of Health's National Institute of General Medical Sciences, notes that government funding has been available for over a decade.

In addition, there is one special program scheduled as part of the NIH's Roadmap for Medical Research to establish centers of innovation for expressing membrane proteins.

Third, challenging proteins are to be the focus of new, specialized centers to be established within PSI. Project proposals are currently being solicited, either from academia or industrial applicants, with evaluations to be completed next spring.

In Europe, a consortium like the one Stewart proposes already exists. Launched in 2001, MePNet, for Membrane Protein Network, is trying to improve structural genomic technology to probe GPCRs. The group is made up of four academic research teams in France and Germany and is coordinated by Bio-Xtal, a French biotech start-up. According to MePNet, drug industry funders include Wyeth, Boehringer Ingelheim, Genencor, GlaxoSmithKline, Merck KGaA, Novo Nordisk, and Sanwa Kagaku Kenkyusho.

Today, resolving the TATA-box binding protein would be much quicker, although protein-nucleic acid complexes still remain a challenge.