1QJ0

HUMAN INSULIN HEXAMERS WITH CHAIN B HIS MUTATED TO TYR

Summary for 1QJ0

• Entry DOI: 10.2210/pdb1qj0/pdb
• Related: 1QIY 1QIZ
• Descriptor: INSULIN A CHAIN, INSULIN B CHAIN, ZINC ION, ... (5 entities in total)
• Functional Keywords: hormone, glucose metabolism, diabetes, insulin mutant
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 4
• Total formula weight: 11851.63

Authors

Tang, L.,Whittingham, J.L.,Verma, C.S.,Caves, L.S.D.,Dodson, G.G. (deposition date: 1999-06-18, release date: 1999-06-22, Last modification date: 2024-10-16)

Primary citation

Tang, L.,Whittingham, J.L.,Verma, C.S.,Caves, L.S.D.,Dodson, G.G.
Structural Consequences of the B5 Histidine --> Tyrosine Mutation in Human Insulin Characterized by X-Ray Crystallography and Conformational Analysis.
Biochemistry, 38:12041-, 1999

PubMed Abstract: The addition of phenols to hexameric insulin solutions produces a particularly stable hexamer, resulting from a rearrangement in which residues B1-B8 change from an extended conformation (T-state) to form an alpha-helix (R-state). The R-state is, in part, stabilized by nonpolar interactions between the phenolic molecule and residue B5 His at the dimer-dimer interface. The B5 His --> Tyr mutant human insulin was constructed to see if the tyrosine side chain would mimic the effect of phenol binding in the hexamer and induce the R-state. In partial support of this hypothesis, the molecule crystallized as a half-helical hexamer (T(3)R(3)) in conditions that conventionally promote the fully nonhelical (T6) form. As expected, in the presence of phenol or resorcinol, the B5 Tyr hexamers adopt the fully helical (R6) conformation. Molecular modeling calculations were performed to investigate the conformational preference of the T-state B5 Tyr side chain in the T(3)R(3) form, this side chain being associated with structural perturbations of the A7-A10 loop in an adjacent hexamer. For an isolated dimer, several different orientations of the side chain were found, which were close in energy and readily interconvertible. In the crystal environment only one of these conformations remains low in energy; this conformation corresponds to that observed in the crystal structure. This suggests that packing constraints around residue B5 Tyr result in the observed structural rearrangements. Thus, rather than promoting the R-state in a manner analogous to phenol, the mutation appears to destabilize the T-state. These studies highlight the role of B5 His in determining hexamer conformation and in mediating crystal packing interactions, properties that are likely be important in vivo.

PubMed: 10508408
DOI: 10.1021/BI990700K

Experimental method

X-RAY DIFFRACTION (2.4 Å)