Conformational correlation and coupled motion between residue A21 and B25 side chain observed in crystal structures of insulin mutants at position A21

The C-terminal residue of the insulin A chain is invariant and kept as aspa ragine in all known insulin molecules from hagfish through birds to mammals . To get information on the role of this conserved residue, which is still unclear, the three-dimensional structures of four human insulin mutants, A2 1 Asn --> Gly, A21 Asn --> Asp, A21 Asn --> Ala, and A21 Asn --> Gln DesB30 , were determined by X-ray crystallography. The four mutants crystallize se parately into two kinds (rhombohedral and cubic) of crystals. In the refine d structures, conformational correlation and coupled motion between the A c hain C-terminal residue A21 and the B25 side chain was observed, in contras t to the nearly unchanged general structures as compared with the native in sulin structures in their respective crystals. A detailed analysis suggests that residue A21 can affect insulin receptor binding by interaction with t he B25 side chain and the B chain C-terminal segment to assist the B25 side chain rearranging into the 'active' conformation. (C) 2000 Elsevier Scienc e B.V. All rights reserved.