Structure of a protein in a kinetic trap.
We have determined the structure of a metastable disulphide isomer of human insulin. Although not observed for proinsulin folding or insulin-chain recombination, the isomer retains ordered secondary structure and a compact hydrophobic core. Comparison with native insulin reveals a global rearrangement in the orientation of A- and B-chains. One face of the protein's surface is nevertheless in common between native and non-native structures. This face contains receptor-binding determinants, rationalizing the partial biological activity of the isomer. Structures of native and non-native disulphide isomers also define alternative three-dimensional templates. Threading of insulin-like sequences provide an experimental realization of the inverse protein-folding problem.
Hua
Q X
QX
Department of Biochemistry and Molecular Biology, University of Chicago, Illinois 60637-5419, USA.
Gozani
S N
SN
Chance
R E
RE
Hoffmann
J A
JA
Frank
B H
BH
Weiss
M A
MA
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011384:Proinsulin / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011972:Receptor, Insulin / Q000378:metabolism; D013698:Templates, Genetic; D013816:Thermodynamics
D007328:Insulin; D011384:Proinsulin; D011972:Receptor, Insulin