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PDBsum entry 1mhj

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protein Protein-protein interface(s) links
Hormone PDB id
1mhj
Jmol
Contents
Protein chains
21 a.a.
29 a.a.
PDB id:
1mhj
Name: Hormone
Title: Solution structure of the superactive monomeric des- [phe(b25)] human insulin mutant. Elucidation of the structural basis for the monomerization of the des- [phe(b25)] insulin and the dimerization of native insulin
Structure: Insulin. Chain: a. Engineered: yes. Mutation: yes. Insulin. Chain: b. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
NMR struc: 20 models
Authors: A.M.M.Jorgensen,H.B.Olsen,J.J.Led,P.Balschmidt
Key ref:
A.M.Jørgensen et al. (1996). Solution structure of the superactive monomeric des-[Phe(B25)] human insulin mutant: elucidation of the structural basis for the monomerization of des-[Phe(B25)] insulin and the dimerization of native insulin. J Mol Biol, 257, 684-699. PubMed id: 8648633 DOI: 10.1006/jmbi.1996.0194
Date:
30-Nov-94     Release date:   15-Oct-95    
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: 10.1006/jmbi.1996.0194 J Mol Biol 257:684-699 (1996)
PubMed id: 8648633  
 
 
Solution structure of the superactive monomeric des-[Phe(B25)] human insulin mutant: elucidation of the structural basis for the monomerization of des-[Phe(B25)] insulin and the dimerization of native insulin.
A.M.Jørgensen, H.B.Olsen, P.Balschmidt, J.J.Led.
 
  ABSTRACT  
 
The three-dimensional solution structure of des-[Phe(B25)] human insulin has been determined by nuclear magnetic resonance spectroscopy and restrained molecular dynamics calculations. Thirty-five structures were calculated by distance geometry from 581 nuclear Overhauser enhancement-derived distance constraints, ten phi torsional angle restraints, the restraints from 16 helical hydrogen bonds, and three disulfide bridges. The distance geometry structures were optimized using simulated annealing and restrained energy minimization. The average root-mean-square (r.m.s.) deviation for the best 20 refined structures is 1.07 angstroms for the backbone and 1.92 angstroms for all atoms if the less well-defined N and C-terminal residues are excluded. The helical regions are more well defined, with r.m.s. deviations of 0.64 angstroms for the backbone and 1.51 angstroms for all atoms. It is found that the des-[Phe(B25)] insulin is a monomer under the applied conditions (4.6 to 4.7 mM, pH 3.0, 310 K), that the overall secondary and tertiary structures of the monomers in the 2Zn crystal hexamer of native insulin are preserved, and that the conformation-averaged NMR solution structure is close to the structure of molecule 1 in the hexamer. The structure reveals that the lost ability of des-[Phe(B25)] insulin to self-associate is caused by a conformational change of the C-terminal region of the B-chain, which results in an intra-molecular hydrophobic interaction between Pro(B28) and the hydrophobic region Leu(B11)-Leu(B15) of the B-chain alpha-helix. This interaction interferes with the inter-molecular hydrophobic interactions responsible for the dimerization of native insulin, depriving the mutant of the ability to dimerize. Further, the structure displays a series of features that may explain the high potency of the mutant on the basis of the current model for the insulin-receptor interaction. These features are: a change in conformation of the C-terminal region of the B-chain, the absence of strong hydrogen bonds between this region and the rest of the molecule, and a relatively easy accessibility to the Val(A3) residue.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Primary structure of the des-[Phe(B25)] mutant of human insulin.
Figure 7.
Figure 7. The mean solution structure of des-[Phe(B25)] insulin. Only the two backbones (A-chain and B-chain) are shown.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1996, 257, 684-699) copyright 1996.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19086273 E.E.Büllesbach, M.A.Hass, M.R.Jensen, D.F.Hansen, S.M.Kristensen, C.Schwabe, and J.J.Led (2008).
Solution structure of a conformationally restricted fully active derivative of the human relaxin-like factor.
  Biochemistry, 47, 13308-13317.
PDB codes: 2k6t 2k6u
18040865 W.Bocian, J.Sitkowski, E.Bednarek, A.Tarnowska, R.Kawecki, and L.Kozerski (2008).
Structure of human insulin monomer in water/acetonitrile solution.
  J Biomol NMR, 40, 55-64.
PDB code: 2jv1
18491415 W.Bocian, P.Borowicz, J.Mikołajczyk, J.Sitkowski, A.Tarnowska, E.Bednarek, T.Głabski, B.Tejchman-Małecka, M.Bogiel, and L.Kozerski (2008).
NMR structure of biosynthetic engineered human insulin monomer B31(Lys)-B32(Arg) in water/acetonitrile solution. Comparison with the solution structure of native human insulin monomer.
  Biopolymers, 89, 820-830.
PDB code: 2rn5
16365033 K.J.Rosengren, F.Lin, R.A.Bathgate, G.W.Tregear, N.L.Daly, J.D.Wade, and D.J.Craik (2006).
Solution structure and novel insights into the determinants of the receptor specificity of human relaxin-3.
  J Biol Chem, 281, 5845-5851.
PDB code: 2fhw
16080143 V.Zoete, M.Meuwly, and M.Karplus (2005).
Study of the insulin dimerization: binding free energy calculations and per-residue free energy decomposition.
  Proteins, 61, 79-93.  
11343787 J.Ye, W.Chang, and D.Liang (2001).
Crystal structure of destripeptide (B28-B30) insulin: implications for insulin dissociation.
  Biochim Biophys Acta, 1547, 18-25.
PDB code: 1htv
11123908 S.H.Nakagawa, H.S.Tager, and D.F.Steiner (2000).
Mutational analysis of invariant valine B12 in insulin: implications for receptor binding.
  Biochemistry, 39, 15826-15835.  
9566117 C.McInnes, and B.D.Sykes (1997).
Growth factor receptors: structure, mechanism, and drug discovery.
  Biopolymers, 43, 339-366.  
9235985 X.Chang, A.M.Jorgensen, P.Bardrum, and J.J.Led (1997).
Solution structures of the R6 human insulin hexamer,.
  Biochemistry, 36, 9409-9422.
PDB codes: 1ai0 1aiy
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.