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PDBsum entry 4ak0

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protein Protein-protein interface(s) links
Hormone PDB id
4ak0
Jmol
Contents
Protein chains
21 a.a.
29 a.a.
Waters ×24
PDB id:
4ak0
Name: Hormone
Title: Ligand controlled assembly of hexamers, dihexamers, and line multihexamer structures by an engineered acylated insulin
Structure: Insulin a chain. Chain: a. Engineered: yes. Insulin b chain. Chain: b. Fragment: delta b30, residues 25-53. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Expression_system_taxid: 4932
Resolution:
2.28Å     R-factor:   0.172     R-free:   0.231
Authors: D.B.Steensgaard,G.Schluckebier,H.M.Strauss,M.Norrman,J.K.Tho A.V.Friderichsen,S.Havelund,I.Jonassen
Key ref: D.B.Steensgaard et al. (2013). Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec. Biochemistry, 52, 295-309. PubMed id: 23256685 DOI: 10.1021/bi3008609
Date:
21-Feb-12     Release date:   09-Jan-13    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
21 a.a.
Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
29 a.a.
Key:    PfamA domain  Secondary structure

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biochemical function     hormone activity     1 term  

 

 
DOI no: 10.1021/bi3008609 Biochemistry 52:295-309 (2013)
PubMed id: 23256685  
 
 
Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec.
D.B.Steensgaard, G.Schluckebier, H.M.Strauss, M.Norrman, J.K.Thomsen, A.V.Friderichsen, S.Havelund, I.Jonassen.
 
  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.