Organogold complexes probe a large beta-barrel cavity for human serum alpha1-acid glycoprotein.
Human alpha(1)-acid glycoprotein (AAG) is an acute phase component of the plasma, binding numerous drugs and natural compounds with high-affinity. Using circular dichroism (CD) spectroscopy, strong AAG binding of organogold complexes was found, the molecular size and chemical structure of which differ from known AAG binding agents. The 16-membered Au(2)P(4)C(8)O(2) macrocycles interconvert rapidly between two helical forms and produce enantiomeric conformations which are in dynamic equilibrium in solution. AAG binds preferentially one of the chiral conformers as indicated by strong Cotton effects generated by intramolecular exciton coupling between the pairs of hetercyclic chromophores. Lipophilic nature of the guest molecules suggests the dominant contribution of hydrophobic interactions in the AAG binding. Comparison of the main genetic variants of AAG revealed that both the 'F1/S' and 'A' variants bind with high-affinity the gold(I) macrocycles (K(a) approximately 10(6) M(-1)). CD/fluorescence displacement, and fluorescence quenching experiments indicated inclusion of the compounds into the central beta-barrel cavity of AAG of which exact tertiary structure is yet unknown. Molecular dimensions of the gold(I) macrocycles (13 x 14 x 14 A) indicate that the principal ligand binding cavity of both the 'F1/S' and 'A' variants must be larger compared to the models published to date. Based on these findings, a novel homology model of AAG 'F1' variant was constructed using the human neutrophil gelatinase-associated lipocalin as a template. The organogold complexes were successfully docked into the central cavity of this model.
Zsila
Ferenc
F
Institute of Biomolecular Chemistry, Chemical Research Center, Budapest, P.O. Box 17, H-1525, Hungary. zsferi@chemres.hu
Bikádi
Zsolt
Z
Hazai
Eszter
E
Simon
Agnes
A
Fitos
Ilona
I
Mády
György
G
D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D015335:Molecular Probes; D015394:Molecular Structure; D050607:Organogold Compounds / Q000737:chemistry*; D009961:Orosomucoid / Q000737:chemistry*; D011487:Protein Conformation; D013056:Spectrophotometry, Ultraviolet
D015335:Molecular Probes; D050607:Organogold Compounds; D009961:Orosomucoid