University of California

Chiron Corporation

Judith C Hempel

Bradford W Gibson

Irwin D Kuntz

Eric W Taylor

Gavin D Dollinger

Connie M Oshiro

Malin Young

Ning Tang

The present invention provides a fast and efficient method for determining the three-dimensional conformation of a protein. The steps of the method of the invention include: 1) formation of physical distance constraints, e.g., forming intramolecular chemical crosslinks of known size between residues of a protein; 2) enriching the number of the molecules that have intramolecular chemical crosslinks in the reaction pool, e.g., using size separation to remove proteins with intermolecular bonds; 3) exposing the enriched reaction pool to a protease that cuts the protein at specific sites to produce peptide fragments; 4) measuring the size of the peptide fragments to determine linkage sites with a certain spatial relationship in the protein; and 5)interpreting the data produced to determine spatial geometry and protein structure based on the deduced spatial relationship of the linkage sites. The information is preferably analyzed with aid from a computer system, which can be used to generate and/or analyze distance constraints between amino acids.

Method of determining the three-dimensional shape of a macromolecule

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San Francisco, CA, United States of America

Judith C Hempel