2WRU

Semi-synthetic highly active analogue of human insulin NMeAlaB26-DTI- NH2

Summary for 2WRU

• Entry DOI: 10.2210/pdb2wru/pdb
• Related: 1A7F 1AI0 1AIY 1B9E 1BEN 1EFE 1EV3 1EV6 1EVR 1FU2 1FUB 1G7A 1G7B 1GUJ 1HIQ 1HIS 1HIT 1HLS 1HTV 1HUI 1IOG 1IOH 1J73 1JCA 1JCO 1K3M 1KMF 1LKQ 1LPH 1MHI 1MHJ 1MSO 1OS3 1OS4 1Q4V 1QIY 1QIZ 1QJ0 1RWE 1SF1 1SJT 1T0C 1T1K 1T1P 1T1Q 1TRZ 1TYL 1TYM 1UZ9 1VKT 1W8P 1XDA 1XGL 1XW7 1ZEG 1ZEH 1ZNJ 2AIY 2C8Q 2C8R 2CEU 2H67 2HH4 2HHO 2HIU 2VJZ 2VK0 2WBY 2WC0 2WRV 2WRW 2WRX 2WS0 2WS1 2WS4 2WS6 2WS7 3AIY 4AIY 5AIY
• Descriptor: INSULIN A CHAIN, INSULIN B CHAIN, ACETATE ION, ... (4 entities in total)
• Functional Keywords: carbohydrate metabolism, glucose metabolism, hormone, analogue, diabetes mellitus
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 2
• Total formula weight: 5428.18

Authors

Brzozowski, A.M.,Jiracek, J.,Zakova, L.,Antolikova, E.,Watson, C.J.,Turkenburg, J.P.,Dodson, G.G. (deposition date: 2009-09-02, release date: 2010-02-09, Last modification date: 2023-12-20)

Primary citation

Jiracek, J.,Zakova, L.,Antolikova, E.,Watson, C.J.,Turkenburg, J.P.,Dodson, G.G.,Brzozowski, A.M.
Implications for the Active Form of Human Insulin Based on the Structural Convergence of Highly Active Hormone Analogues.
Proc.Natl.Acad.Sci.USA, 107:1966-, 2010

PubMed Abstract: 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.

PubMed: 20133841
DOI: 10.1073/PNAS.0911785107

Experimental method

X-RAY DIFFRACTION (1.57 Å)