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netLibrary - eBook Summary Structure-based Drug Design by ...

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binding and are colored light gray in Figure 5. In contrast, the [Asp175, Glu178,179] rarrow.gif<br />

Ala175,178,179 cluster mutation showed a 12-fold loss in bradykinin binding affinity, and the [Glu282, Asp 286] rarrow.gif Ala 282,286 cluster mutation lost 17-fold with respect to the wild type receptor. The<br />

Page 134<br />

Asp 268 rarrow.gif Ala 268 and Asp 286 rarrow.gif Ala 286 point mutations caused 19-and 28-fold<br />

respective losses in affinity for bradykinin. Close inspection of the bradykinin Arg 1 side chain location<br />

and surrounding receptor interactions led to the suspicion that Asp 286 and Asp 268<br />

Figure 5<br />

Proposed model of bradykinin bound to the rat B2 receptor at the agonist binding site.<br />

Only the upper portion of the receptor is shown as gray helical ribbons. Bradykinin<br />

backbone and side chain atoms are shown as thick white licorice. Positions of point<br />

mutations having no significant adverse effects on bradykinin binding are shown as<br />

light gray spheres. Positions of mutations affecting bradykinin binding are shown as<br />

dark gray spheres.<br />

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