Perspective

Trapping Moving Targets with Small Molecules

Science  10 Apr 2009:
Vol. 324, Issue 5924, pp. 213-215
DOI: 10.1126/science.1169378

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  1. Fig. 1.

    (A) Shallow wells and transitional barriers of a dynamic free-energy landscape allow a macromolecule to sample multiple preexisting conformational states, corresponding to the catalytically active (green) and inactive (blue, red, yellow, and gray) forms. The global energy minimum shifts to favor the inactive conformation (red) when an inhibitor (cyan star) binds to an allosteric site. (B) The active (green) and inactive (red) conformations schematically represent a small enzyme, consisting of a flexible loop connecting two helices. Both conformations are in equilibrium while the enzyme is in the apo state. A native substrate (orange triangle) binds to the active site located between the two helices. Alternatively, a small molecule (cyan star) binds to a region within the flexible loop of the inactive conformer, allosterically inhibiting the enzyme. (C) Overlaid theoretical 15N-HSQC spectra display peaks corresponding to backbone amides of residues in selected regions of the enzyme, numbered 1 to 4. Green and pink peaks represent the apo active and inactive conformers (left); orange and cyan peaks represent the bound active and inactive conformers (right), respectively. As depicted, peak 1 of the active and inactive conformations is located in the same helix of both conformations and is superimposible (purple box), whereas peaks 2 to 4 correspond to regions within the flexible loop region. Upon native substrate binding at the active site, only peak 1 of the active conformation shifts to a new location (orange box). Similarly, only peak 2 of the inactive conformation (cyan box) is perturbed when a small-molecule inhibitor binds at an allosteric site.