Visualization of the Top-Scoring Mutant Structure (IMAGE)
Caption
This image is a visualization of the 3-D crystal structure of the top-scoring DHFR protein mutant, determined from experimental data. DHFR is a likely molecule for attack by a drug to stop MRSA bacteria infections. The new K* Algorithm predicted both the structures of the mutants and affinity, how well the mutants would interact both with the inhibitor drug molecule and the native substrate. Scientists' next step would be to redesign the inhibitor or design a new inhibitor that better binds to the mutant DHFR protein, as predicted by Algorithm K*, as well as to the wild-type MRSA bacterium DHFR. Alternately, they may try to design a new inhibitor that would bind better to the mutant DHFR proteins predicted by K*, and use a combination therapy of the Old inhibitor (which binds well to the wild-type MSRA DHFR) plus the New inhibitor, to block mutants that may come along over time. These mutations (shown as stick residues) cause an 18-fold loss in affinity, and crystal structures show a conformation with significantly reduced protein:inhibitor interactions. The mutations are the colored (green and red) sticks that stick out of the rainbow-colored ribbon drawing of the DHFR protein. The mutations are in two places because the mutant has two amino acid mutations.
Credit
Image Courtesy of Bruce R. Donald, Duke Univ. Medical Center
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