Document Detail

Inactive conformation of an insulin despite its wild-type sequence.
MedLine Citation:
PMID:  9070440     Owner:  NLM     Status:  MEDLINE    
The peptide group between residues B24 and B25 of insulin was replaced by an ester bond. This modification only in the backbone was meant to eliminate a structurally important H-bond between the amide proton of B25 and the carbonyl oxygen of A19, and consequently to enhance detachment of the C-terminal B-chain from the body of the molecule, exposing the underlying A-chain. According to a model derived from the effects of side-chain substitutions, main-chain shortening, and crosslinking, this conformational change is prerequisite for receptor binding. Contrary to the expectation that increased flexibility would increase receptor binding and activity, depsi-insulin ([B24-B25 CO-O]insulin) has turned out be only 3-4% potent. In search of an explanation for this observation, the solution structure of depsi-insulin was determined by two-dimensional 1H-NMR spectroscopy. It was found that the loss of the B25-A19 H-bond does not entail detachment of the C-terminal B-chain. On the contrary, it is overcompensated by a gain in hydrophobic interaction achieved by insertion of the Phe B25 side chain into the molecule's core. This is possible because of increased rotational freedom in the backbone owing to the ester bond. Distortion of the B20-B23 turn and an altered direction of the distal B-chain are consequences that also affect self-association. The exceptional position of the B25 side chain is thus the key feature of the depsi-insulin structure. Being buried in the interior, it is not available for guiding the interaction with the receptor, a crucial role attributed to it by the model. This seems to be the main reason why the structure of depsi-insulin represents an inactive conformation.
G Kurapkat; E De Wolf; J Grötzinger; A Wollmer
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  6     ISSN:  0961-8368     ISO Abbreviation:  Protein Sci.     Publication Date:  1997 Mar 
Date Detail:
Created Date:  1997-05-27     Completed Date:  1997-05-27     Revised Date:  2010-09-13    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  580-7     Citation Subset:  IM    
Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
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MeSH Terms
Amino Acid Sequence
Insulin / chemistry*
Magnetic Resonance Spectroscopy
Molecular Sequence Data
Protein Structure, Secondary
Protein Structure, Tertiary
Receptor, Insulin / chemistry
Reg. No./Substance:
11061-68-0/Insulin; EC, Insulin

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

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