2WRW: Semi-Synthetic Highly Active Analogue Of Human Insulin D- Prob26-Dti-Nh2

Insulin is a key protein hormone that regulates blood glucose levels and, thus, has widespread impact on lipid and protein metabolism. Insulin action is manifested through binding of its monomeric form to the Insulin Receptor (IR). At present, however, our knowledge about the structural behavior of insulin is based upon inactive, multimeric, and storage-like states. The active monomeric structure, when in complex with the receptor, must be different as the residues crucial for the interactions are buried within the multimeric forms. Although the exact nature of the insulin's induced-fit is unknown, there is strong evidence that the C-terminal part of the B-chain is a dynamic element in insulin activation and receptor binding. Here, we present the design and analysis of highly active (200-500%) insulin analogues that are truncated at residue 26 of the B-chain (B(26)). They show a structural convergence in the form of a new beta-turn at B(24)-B(26). We propose that the key element in insulin's transition, from an inactive to an active state, may be the formation of the beta-turn at B(24)-B(26) associated with a trans to cis isomerisation at the B(25)-B(26) peptide bond. Here, this turn is achieved with N-methylated L-amino acids adjacent to the trans to cis switch at the B(25)-B(26) peptide bond or by the insertion of certain D-amino acids at B(26). The resultant conformational changes unmask previously buried amino acids that are implicated in IR binding and provide structural details for new approaches in rational design of ligands effective in combating diabetes.
PDB ID: 2WRWDownload
MMDB ID: 79873
PDB Deposition Date: 2009/9/2
Updated in MMDB: 2012/06
Experimental Method:
x-ray diffraction
Resolution: 2.41  Å
Source Organism:
Similar Structures:
Biological Unit for 2WRW: tetrameric; determined by author and by software (PISA)
Molecular Components in 2WRW
Label Count Molecule
Proteins (4 molecules)
Insulin a Chain(Gene symbol: INS)
Molecule annotation
Insulin B Chain(Gene symbol: INS)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB