Learning how SARS spikes ...( mutations in the spike protein that aff...)

"One of the critical issues in a SARS epidemic would be to predict whether a given variant of the virus will jump species or move laterally from one human to the other. Understanding the structure of this complex will help us understand what these mutations in the spike protein mean in terms of infectivity," Harrison said.

According to Harrison, Farzan and his colleagues laid the scientific groundwork for determining the structure of the spike-ACE2 complex. In 2003, Farzan's team discovered that the ACE2 protein is the receptor for the SARS virus. They also identified a specific fragment of the spike protein that is involved in viral attachment.

As a result of those studies, researchers in Harrison's and Farzan's laboratories could concentrate their efforts on creating crystals of the relevant fragments of the spike protein in complex with the ACE2 receptor. After they had crystallized the protein complex, the crystals were then subjected to structural analysis using x-ray crystallography. In this widely used technique, x-rays are directed through crystals of a protein. The resulting diffraction pattern is analyzed to deduce the atomic structure of the protein or protein complex under study.

The x-ray structure revealed that the spike protein fragment showed a slightly concave surface that fits a complementary surface on the receptor, said Harrison. There was nothing surprising about the interaction itself, he noted. However, the studies revealed important new information about two specific amino acids on the spike protein. These were the amino acids that Farzan and his colleagues had previously determined to be the most critical for determining how the SARS virus adapted from infecting only civets to infecting humans.

"Both of these critical amino acids turned out to be right in the middle of the interface between the spike protein and the receptor," said Harrison.
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
15-Sep-2005