3ZS2

TyrB25,NMePheB26,LysB28,ProB29-insulin analogue crystal structure

Summary for 3ZS2

• Entry DOI: 10.2210/pdb3zs2/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 2W44 2WBY 2WC0 2WRU 2WRV 2WRW 2WRX 2WS0 2WS1 2WS4 2WS6 2WS7 3AIY 3ZQR 3ZU1 4AIY 5AIY
• Descriptor: INSULIN A CHAIN, INSULIN B CHAIN, PHENOL, ... (6 entities in total)
• Functional Keywords: carbohydrate metabolism, glucose metabolism, hormone, diabetes mellitus
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 12
• Total formula weight: 35756.46

Authors

Antolikova, E.,Zakova, L.,Turkenburg, J.P.,Watson, C.J.,Hanclova, I.,Sanda, M.,Cooper, A.,Kraus, T.,Brzozowski, A.M.,Jiracek, J.A. (deposition date: 2011-06-21, release date: 2011-08-31, Last modification date: 2023-12-20)

Primary citation

Antolikova, E.,Zakova, L.,Turkenburg, J.P.,Watson, C.J.,Hanclova, I.,Sanda, M.,Cooper, A.,Kraus, T.,Brzozowski, A.M.,Jiracek, J.A.
Non-Equivalent Role of Inter- and Intramolecular Hydrogen Bonds in the Insulin Dimer Interface.
J.Biol.Chem., 286:36968-, 2011

PubMed Abstract: Apart from its role in insulin receptor (IR) activation, the C terminus of the B-chain of insulin is also responsible for the formation of insulin dimers. The dimerization of insulin plays an important role in the endogenous delivery of the hormone and in the administration of insulin to patients. Here, we investigated insulin analogues with selective N-methylations of peptide bond amides at positions B24, B25, or B26 to delineate their structural and functional contribution to the dimer interface. All N-methylated analogues showed impaired binding affinities to IR, which suggests a direct IR-interacting role for the respective amide hydrogens. The dimerization capabilities of analogues were investigated by isothermal microcalorimetry. Selective N-methylations of B24, B25, or B26 amides resulted in reduced dimerization abilities compared with native insulin (K(d) = 8.8 μM). Interestingly, although the N-methylation in [NMeTyrB26]-insulin or [NMePheB24]-insulin resulted in K(d) values of 142 and 587 μM, respectively, the [NMePheB25]-insulin did not form dimers even at high concentrations. This effect may be attributed to the loss of intramolecular hydrogen bonding between NHB25 and COA19, which connects the B-chain β-strand to the core of the molecule. The release of the B-chain β-strand from this hydrogen bond lock may result in its higher mobility, thereby shifting solution equilibrium toward the monomeric state of the hormone. The study was complemented by analyses of two novel analogue crystal structures. All examined analogues crystallized only in the most stable R(6) form of insulin oligomers (even if the dimer interface was totally disrupted), confirming the role of R(6)-specific intra/intermolecular interactions for hexamer stability.

PubMed: 21880708
DOI: 10.1074/JBC.M111.265249

Experimental method

X-RAY DIFFRACTION (1.97 Å)