Bound conformation

In the cAMP-bound conformation, cAMP-GEFs specifically bind to Ras-like small GTPases and activate these proteins by profoundly accelerating the exchange of GDP for GTP. 

It is important to note that most molecules are not rigid but may prefer a distrinct structure and the conformation of a molecule strongly depends on its specific environment. Hence, the crystal structure of a drug does not have to correspond to the receptor bound conformation. Also, a conformation in solution depends on the nature of the solvent and measuring conditions, and may change when the molecule is bound to the receptor [4]. In addition, different receptors or receptor subtypes can bind the same drug in different conformations. It is a general assumption and observation, but by far not a strict condition, that the conformation in aqueous solution is similar to the bound conformation and is a better representation of the bioactive conformation than an X-ray structure of the isolated molecule in the crystalline state. 

An upper limit for dissociation constants in the rtiQUmolar range is mainly given by the solubility of receptor or ligand and the occurrence of nonspecific binding processes which make the determination of a single bound conformation obsolete. 

Figure 2 Spatial overlap of low energy conformers of H-Hat-D-O rn-Aic-Glu-NH2 (heavy lines) with proposed models of the p-receptor-bound conformation (light lines) based on conformational analysis of H-Tyr-D-0 rn-Phe-As p-NH2 [24] (left panel) and H-Tyr-Pro-Phe(NMe)-D-Pro-NH2 (PL017) [29] (right panel). 

This model of the receptor-bound conformation of TIP is characterized by a clustered configuration of the three aromatic moieties with the Phe3 aromatic ring sandwiched between the Tyr1 and Tic2 aromatic rings. 

Wilkes BC, Schiller, PW. Comparative analysis of various proposed models of the receptor-bound conformation of TIP(P)-related opioid antagonists. Biopolymers (Peptide Sci) 1995 37 391-400. 

Wilkes BC, Nguyen TM-D, Weltrowska G, Carpenter KA, Lemieux C, Chung NN, Schiller PW. The receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH related -opioid antagonists contains all trans peptide bonds. J Peptide Res 1998 51 386-394. 

The difference in activity of the E and Z olefins against HRV-14 was explained by examining the relatively low energy virus-bound conformations. The result of an overlay of WIN-54954 (based on x-ray crystallography data), minimize E- and Z-olefinic structures and the butyne analogue, suggested that the E isomer showed a reasonable fit while the Z isomer did not. Furthermore, when the Z isomer was inserted into the HRV-14 pocket, unfavorable interactions occurred. 

Other enzyme-substrate or inhibitor interaction studies80 82 have been addressed, using a combination of STD and trNOE NMR experiments, in order to collect details on the substrate bound conformation (ligand perspective). In other cases, the availability of a labelled protein receptor83 have permitted to follow the induced chemical shift variations of the protein resonances upon ligand addition to the NMR tube by HSQC methods (protein perspective). 

Poly electrolytes, once adsorbed, undergo conformational changes which usually involve them adopting a more tightly bound conformation. This process causes the counter ion of the polyelectrolyte to... 

Figure 14.4 Bound conformation of the SLex tetrasaccharide compared to that of an efficient fucosyl glycopeptide mimetic compound.81 Tightly bound hydroxyl groups are shown as spheres.

A nice example of an indirect structure determination using the trNOE method is the study of the conformation of a loop of the membrane protein bacteriorhodopsin (BR) [28]. Antibodies were raised against BR, and subsequently the complex of a heptapetide derived from BR was studied in complex with the antibody by trNOE. The bound conformation is a reasonably good representation of the conformation of the peptide in its native state in BR. 

CCR is easily measured by heteronuclear NMR experiments of isotopically labeled molecules. The information extracted from these experiments will significantly improve the resolution of NMR structures, especially bound conformations of weakly bound ligands, since /-couplings cannot be used in this case. The reason is the fact that the nonbound conformation significantly contributes to the averaged values of the coupling constant. 

In the case of a ligand that is weakly bound to a macromolecule in the fast exchange regime, the CCR rates are averaged with the population of free and bound conformation in analogy to the previously described trNOE (Sect 16.3) [50, 51]. 

Interestingly, one of the conformers obtained from data analysis corresponds to the bound conformation of the same chain in a biantennary oligosaccharide-lectin complex from X-ray diffraction. 

Figure 4.8 Erythropoietin. Source Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation, Nature Structural Biology 5 861-866 (1998).)...

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