title: Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus.
abstract: The solution structure of a diabetes-associated mutant human insulin (insulin Los Angeles; PheB24-->Ser) was determined by 13C-edited NMR spectroscopy and distance-geometry/simulated annealing calculations. Among vertebrate insulins PheB24 is invariant, and in crystal structures the aromatic ring appears to anchor the putative receptor-binding surface through long-range packing interactions in the hydrophobic core. B24 substitutions are of particular interest in relation to the mechanism of receptor binding. In one analogue ([GlyB24]insulin), partial unfolding of the B chain has been observed with paradoxical retention of near-native bioactivity. The present study of [SerB24]insulin extends this observation: relative to [GlyB24]insulin, near-native structure is restored despite significant loss of function. To our knowledge, our results provide the first structural study of a diabetes-associated mutant insulin and support the hypothesis that insulin undergoes a change in conformation on receptor binding.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
authors.forename: Q X
authors.initials: QX
authors.lastname: Hua
authors.forename: S E
authors.initials: SE
authors.lastname: Shoelson
authors.forename: K
authors.initials: K
authors.lastname: Inouye
authors.forename: M A
authors.initials: MA
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010649:Phenylalanine; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000378:metabolism; D012694:Serine; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D012694:Serine; D010649:Phenylalanine; C040796:insulin, Ser(B24)-; D011972:Receptor, Insulin