Ligands, conformation/binding

Frimurer TM, Peters GH, Iversen LF, Andersen HS, Moller NP, et al. 2003. Ligand-induced conformational changes improved predictions of ligand binding conformations and affinities. Biophys J 84(4) 2273-2281. 

Receptor complex exists in two conformational states, one of which has a preference for ligand binding. Conformational transition state involves a simulataneous shift in the state of all subunits. 

The Hsp90 chaperone is a necessary component of the AHR pathway and seems to anchor the receptor in the cytosol as well as hold the protein in a high affinity ligand-binding conformation ... 

Van Aalten, D.M.F., Findlay, J.B.C., Amadei, A., Berendsen,H.J.C. Essential dynamics of the cellular retinol-binding protein. Evidence for ligand-induced conformational changes. Protein Engin. 8 (1995) 1129-1136. 

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

Helms and McCammon 1997] Helms, V., McCammon, J.A. Kinase Conformations A computational study of the effect of ligand binding. Prot. Sci. 6 (1997) 2336-2343... 

The essential feature of the AAA is a comparison of active and inactive molecules. A commonly accepted hypothesis to explain the lack of activity of inactive molecules that possess the pharmacophoric conformation is that their molecular volume, when presenting the pharmacophore, exceeds the receptor excluded volume. This additional volume apparently is filled by the receptor and is unavailable for ligand binding this volume is termed the receptor essential volume [3]. Following this approach, the density maps for each of the inactive compounds (in their pharm conformations superimposed with that of active compounds) were constructed the difference between the combined inactive compound density maps and the receptor excluded volume represents the receptor essential volume. These receptor-mapping techniques supplied detailed topographical data that allowed a steric model of the D[ receptor site to be proposed. 

The elegant genetic studies by the group of Charles Yanofsky at Stanford University, conducted before the crystal structure was known, confirm this mechanism. The side chain of Ala 77, which is in the loop region of the helix-turn-helix motif, faces the cavity where tryptophan binds. When this side chain is replaced by the bulkier side chain of Val, the mutant repressor does not require tryptophan to be able to bind specifically to the operator DNA. The presence of a bulkier valine side chain at position 77 maintains the heads in an active conformation even in the absence of bound tryptophan. The crystal structure of this mutant repressor, in the absence of tryptophan, is basically the same as that of the wild-type repressor with tryptophan. This is an excellent example of how ligand-induced conformational changes can be mimicked by amino acid substitutions in the protein. 

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