4AK0

Ligand controlled assembly of hexamers, dihexamers, and linear multihexamer structures by an engineered acylated insulin

Summary for 4AK0

• Entry DOI: 10.2210/pdb4ak0/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 3ZS2 3ZU1 4AIY 4AJX 4AJZ 5AIY
• Descriptor: INSULIN A CHAIN, INSULIN B CHAIN (3 entities in total)
• Functional Keywords: hormone
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Secreted: P01308 P01308
• Total number of polymer chains: 2
• Total formula weight: 5716.55

Authors

Steensgaard, D.B.,Schluckebier, G.,Strauss, H.M.,Norrman, M.,Thomsen, J.K.,Friderichsen, A.V.,Havelund, S.,Jonassen, I. (deposition date: 2012-02-21, release date: 2013-01-09, Last modification date: 2023-12-20)

Primary citation

Steensgaard, D.B.,Schluckebier, G.,Strauss, H.M.,Norrman, M.,Thomsen, J.K.,Friderichsen, A.V.,Havelund, S.,Jonassen, I.
Ligand Controlled Assembly of Hexamers, Dihexamers, and Linear Multihexamer Structures by the Engineered Acylated Insulin Degludec.
Biochemistry, 52:295-, 2013

PubMed Abstract: Insulin degludec, an engineered acylated insulin, was recently reported to form a soluble depot after subcutaneous injection with a subsequent slow release of insulin and an ultralong glucose-lowering effect in excess of 40 h in humans. We describe the structure, ligand binding properties, and self-assemblies of insulin degludec using orthogonal structural methods. The protein fold adopted by insulin degludec is very similar to that of human insulin. Hexamers in the R(6) state similar to those of human insulin are observed for insulin degludec in the presence of zinc and resorcinol. However, under conditions comparable to the pharmaceutical formulation comprising zinc and phenol, insulin degludec forms finite dihexamers that are composed of hexamers in the T(3)R(3) state that interact to form an R(3)T(3)-T(3)R(3) structure. When the phenolic ligand is depleted and the solvent condition thereby mimics that of the injection site, the quaternary structure changes from dihexamers to a supramolecular structure composed of linear arrays of hundreds of hexamers in the T(6) state and an average molar mass, M(0), of 59.7 × 10(3) kg/mol. This novel concept of self-assemblies of insulin controlled by zinc and phenol provides the basis for the slow action profile of insulin degludec. To the best of our knowledge, this report for the first time describes a tight linkage between quaternary insulin structures of hexamers, dihexamers, and multihexamers and their allosteric state and its origin in the inherent propensity of the insulin hexamer for allosteric half-site reactivity.

PubMed: 23256685
DOI: 10.1021/BI3008609

Experimental method

X-RAY DIFFRACTION (2.28 Å)