Document Detail


Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus.
MedLine Citation:
PMID:  8421693     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Q X Hua; S E Shoelson; K Inouye; M A Weiss
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  90     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1993 Jan 
Date Detail:
Created Date:  1993-02-18     Completed Date:  1993-02-18     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  582-6     Citation Subset:  IM    
Affiliation:
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Diabetes Mellitus, Type 2 / etiology,  genetics
Humans
Insulin / analogs & derivatives*,  chemistry*,  genetics,  metabolism,  physiology
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Sequence Data
Mutation
Phenylalanine
Protein Conformation
Protein Structure, Secondary
Receptor, Insulin / metabolism
Serine
Structure-Activity Relationship
Chemical
Reg. No./Substance:
11061-68-0/Insulin; 56-45-1/Serine; 63-91-2/Phenylalanine; 89147-46-6/insulin, Ser(B24)-; EC 2.7.10.1/Receptor, Insulin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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