Enzymes—the proteins responsible for chemicalreactions in living cells—change their structure at dizzying speeds.This dynamic action makes them very efficient, but it can also make themdifficult to study. Prof. Irit Sagi of the Weizmann Institute ofScience’s Department of Biological Regulation develops new experimentaltools and procedures to study shape-shifting enzymes in real time and atthe scale of individual atoms.

“For the past ten years, we’ve been especially fascinated by enzymescalled matrix metalloproteinases, or MMPs, that act like molecularscissors. They chop and dice tissue components like collagen andgelatin,” says Prof. Sagi. “We want to understand the molecularmechanisms that drive the chemical reactions of these enzymes.”

Since MMPs play a role in cancer, inflammatory diseases, andautoimmune disorders, Prof. Sagi and her research team investigate waysto inhibit their activity. Their goal is to design new drugs that couldblock the action of specific MMPs. Such drugs could potentialy be usedto treat a wide variety of illnesses, including colon cancer, multiplesclerosis (MS), Crohn’s disease, and rheumatoid arthritis.

Prof. Sagi and her colleagues developed an innovative technique thatenables them to precisely track complex changes as they actually takeplace in an enzyme. The method, which works in a live cell environment,allows the team to identify the movements of single atoms residingwithin the active site of an enzyme molecule. The scientists freeze theprocess at various stages, and then apply techniques borrowed from thefields of x-ray spectroscopy and structural chemical analysis todetermine the configuration of the molecule at each of those stages.

“We can monitor structural changes in real time,” says Prof. Sagi.“Enzymes are dynamic, and if you don’t take this into account when youdesign drugs, that’s part of the reason the drugs may fail.”

Prof. Sagi focused on a member of the MMP enzyme family known asMMP-9, which is produced in metastatic cancer cells and in tissuesattacked by autoimmune disease. Using the research techniques shepioneered in her lab, Prof. Sagi revealed the entire structure of thisenzyme. And after studying MMP-9 in great detail, her team decided todesign special inhibitors to thwart its harmful action.

Prof. Sagi notes that, over the years, several pharmaceuticalcompanies have designed drugs that inhibit matrix metalloproteinases.“But they turned out to be nonselective inhibitors with a broad range ofactivity, and they caused serious side effects in patients in clinicaltrials,” she says. “The challenge is to design drugs that target theseenzymes in a highly selective way.”

Another enzyme that has caught her interest is TNF alpha convertase,which is thought to be involved in many diseases, including cancer. TNFalpha convertase cleaves a protein called PRO-TNF alpha, slicing throughthe part of its structure that attaches it to the inside of the cellwall. The released PRO-TNF is then free to act in the cell. If too muchof this protein is released at once, disease can develop.

Prof. Sagi and her team, along with Dr. Marcos Milla of Roche PaloAlto, LLC, observed the changes that occur in TNF alpha convertase as itmakes contact with PRO-TNF alpha. Their findings could help researchersdevelop drugs that target TNF alpha convertase and reduce PRO-TNFactivity, and which are more effective and less likely to cause sideeffects than current drugs.

Born in Israel, Prof. Sagi received her PhD at Georgetown University.Her return to Israel as a postdoctoral fellow at the Weizmann Institutewas followed by a stint at the Max Planck Institute in Hamburg, afterwhich she joined the Weizmann staff in 1996. She says that sheparticularly values the collaborative spirit of her fellow facultymembers. “The Weizmann Institute is a rather small place and we all worktogether, and some of us even live on campus,” she says. “It’s veryinformal, which contributes to the great atmosphere.”

Prof. Irit Sagi’s research is supported by the Ilse KatzInstitute for Material Sciences and Magnetic Resonance Research; theLeona M. and Harry B. Helmsley Charitable Trust; the Spencer CharitableFund; Cynthia Adelson, Canada; Michael and Rhoda Ambach, Boca Raton, FL;and Dr. Mireille Steinberg, Canada.

Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair.