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Protein Structure Calling Plan

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By Meredith W. Salisbury

Al Edwards was sick of solving structures the same old way. A senior scientist at the University of Toronto, he’s been working on proteins there for the last five years. “The traditional route,” he explains, “is to discover something internally and work on it internally until you make a story, and then publish it.” Estimated time lapse: six, nine, even 12 months, he says.

For Edwards, that simply wasn’t good enough. In addition to what he considers an unacceptably long time to get each structure into the public domain, he decided that the “biology” half of structural biology wasn’t getting due attention. “What has become increasingly apparent to me is that the results of large-scale efforts are not being adequately communicated to the biological community,” he says.

So he hit on an idea that has revolutionized the way his lab works on protein structures — and its success gives him hope that other labs will implement similar strategies.

Whenever his lab nails a protein structure, Edwards, who favors using NMR over crystallization, launches what he calls his “phone-a-friend protocol.” In reality, these aren’t actually friends — they’re usually people he has never even met. With a given structure in hand, Edwards searches around the world to find scientists working on that protein.

Then he calls those researchers, offering a unique collaboration leading to publication: the chance to work with Edwards’ lab to solve protein function and perform analysis, after which the group would publish a joint paper (sometimes, he even offers to give up lead authorship). Edwards promises not to compete on the protein and that after publication the entire project will belong to the biology researchers.

“Usually, by that time, they’re panting,” Edwards says. That’s when he mentions his key condition: “Then we say, ‘You’ve got about two months.’”

For his team, the collaborations are a boost because the biologists often have inhibitors and reagents that prove essential to understanding the structure. And as for getting the word out, Edwards says, “Who better to communicate it to the community than an expert in the field? This person’s going to be going to the meetings, giving lectures, writing reviews.”

In addition, Edwards says, “I truly believe that we’re reducing the cost per structure” with the collaborative model.

Penn State’s Tony Pegg was Edwards’ first “friend.” He got the call in 2001 that Edwards had a crystal structure for spermidine synthetase. Pegg says he was first able to help by confirming that it was indeed the protein Edwards thought it was, and he also had “a very potent inhibitor that binds into its active site … that made it much more interesting from a structural point of view.” To this day, Edwards’ structure remains the only one available for a protein in that class, Pegg says.

“We were able to make a significant amount of progress in a very short amount of time,” Pegg says. In January 2002, less than six months after Edwards contacted Pegg, the collaborative paper was published. And if he got another call like that one, Pegg says, “I’d do it [again] in a flash.”

Like Pegg, most researchers that Edwards winds up contacting are academics. “It’s usually someone who’s worked on a biological system for a decade [and has] an almost encyclopedic knowledge of the protein,” he says. “You look for people who have all the reagents in their lab already, a person who can deliver quickly.”

There are plenty of times when a structure won’t have anyone working on it, Edwards says. And some of the people he calls don’t have time for a collaboration. But when it works, he says, “It’s been a hoot.” He still gets e-mails from researchers he’s tapped for these projects in the past. “These people are passionate about their proteins.”

 

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