Seminar: Designing DNA-Binding Proteins

On Dec. 6, Carl O. Pabo presented a talk on the structure and design of DNA-binding proteins to the Johns Hopkins Department of Biophysics and Biophysical Chemistry.

Pabo, a visiting professor at Harvard University, discovered that several proteins involved in transcription have zinc fingers that allow them to bind to DNA. Pabo began much of his groundbreaking work on protein-DNA interaction while a faculty member at Hopkins from 1982 to 1991.

Pabo discussed his initial crystallographic studies that focused on major DNA-binding proteins. “The discovery of more areas of surface contact was like finding more lottery tickets,“ he said. “We had found more chances to win.“

Pabo said it was clear to him after initial investigations of protein-DNA crystal structures that there is no “simple code“ for recognition. His team pursued geometric analysis and computational modeling of spatial relationships based on the hypothesis that the way a protein approaches DNA may determine the ability for interactions. The group found a wide variety of docking arrangements but discovered the average arrangement had a similar ridge structure.

Pabo then focused on designing new DNA-binding proteins based on observations. His work on engineered zinc fingers, the most abundant and versatile DNA-binding motif in nature, simulated a very complex interaction with diverse applications including targeted DNA cleaving, gene correction, and genome editing.

His current work continues to explore the limits of specificity in zinc finger-DNA interactions for further work in gene editing.

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