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PDBsum entry 1zeh

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protein ligands metals Protein-protein interface(s) links
Hormone PDB id
1zeh
Jmol
Contents
Protein chains
21 a.a.
30 a.a. *
Ligands
CRS ×5
Metals
_CL ×2
_ZN ×2
Waters ×107
* Residue conservation analysis
PDB id:
1zeh
Name: Hormone
Title: Structure of insulin
Structure: Insulin. Chain: a, c. Synonym: b28asp-mcr. Engineered: yes. Mutation: yes. Insulin. Chain: b, d. Synonym: b28asp-mcr. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: saccharomyces cerevisiae. Expression_system_taxid: 4932. Expression_system_taxid: 4932
Biol. unit: Dodecamer (from PQS)
Resolution:
1.50Å     R-factor:   0.159     R-free:   0.193
Authors: J.L.Whittingham,E.J.Edwards,A.A.Antson,J.M.Clarkson, G.G.Dodson
Key ref:
J.L.Whittingham et al. (1998). Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues. Biochemistry, 37, 11516-11523. PubMed id: 9708987 DOI: 10.1021/bi980807s
Date:
01-May-98     Release date:   09-Dec-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
21 a.a.
Protein chains
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin
Seq:
Struc:
110 a.a.
30 a.a.*
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 1 residue position (black cross)

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

 

 
DOI no: 10.1021/bi980807s Biochemistry 37:11516-11523 (1998)
PubMed id: 9708987  
 
 
Interactions of phenol and m-cresol in the insulin hexamer, and their effect on the association properties of B28 pro --> Asp insulin analogues.
J.L.Whittingham, D.J.Edwards, A.A.Antson, J.M.Clarkson, G.G.Dodson.
 
  ABSTRACT  
 
Insulin's natural tendency to form dimers and hexamers is significantly reduced in a mutant insulin B28 Pro --> Asp, which has been designed as a monomeric, rapid-acting hormone for therapeutic purposes. This molecule can be induced to form zinc hexamers in the presence of small phenolic derivatives which are routinely used as antimicrobial agents in insulin preparations. Two structures of B28 Asp insulin have been determined from crystals grown in the presence of phenol and m-cresol. In these crystals, insulin exists as R6 zinc hexamers containing a number of phenol or m-cresol molecules associated with aromatic side chains at the dimer-dimer interfaces. At the monomer-monomer interfaces, the B28 Pro --> Asp mutation leads to increased conformational flexibility in the B chain C termini, resulting in the loss of important intermolecular van der Waals contacts, thus explaining the monomeric character of B28 Asp insulin. The structure of a cross-linked derivative of B28 Asp insulin, containing an Ala-Lys dipeptide linker between residues B30 Ala and A1 Gly, has also determined. This forms an R6 zinc hexamer containing several m-cresol molecules. Of particular interest in this structure are two m-cresol molecules whose binding disrupted the beta-strand in one of the dimers. This observation suggests that the cross-link introduces mechanical strain on the B chain C terminus, thereby weakening the monomer-monomer interactions.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21376731 C.Haupt, M.Bereza, S.T.Kumar, B.Kieninger, I.Morgado, P.Hortschansky, G.Fritz, C.Röcken, U.Horn, and M.Fändrich (2011).
Pattern recognition with a fibril-specific antibody fragment reveals the surface variability of natural amyloid fibrils.
  J Mol Biol, 408, 529-540.  
18607693 C.Poulsen, D.Jacobsen, and L.Palm (2008).
Effect of ethylenediamine on chemical degradation of insulin aspart in pharmaceutical solutions.
  Pharm Res, 25, 2534-2544.  
18676643 H.Vashisth, and C.F.Abrams (2008).
Ligand escape pathways and (un)binding free energy calculations for the hexameric insulin-phenol complex.
  Biophys J, 95, 4193-4204.  
18332129 Q.X.Hua, S.H.Nakagawa, W.Jia, K.Huang, N.B.Phillips, S.Q.Hu, and M.A.Weiss (2008).
Design of an active ultrastable single-chain insulin analog: synthesis, structure, and therapeutic implications.
  J Biol Chem, 283, 14703-14716.
PDB codes: 2jzq 3bxq
18492668 Z.L.Wan, K.Huang, S.Q.Hu, J.Whittaker, and M.A.Weiss (2008).
The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition.
  J Biol Chem, 283, 21198-21210.  
17606621 C.Kuei, S.Sutton, P.Bonaventure, C.Pudiak, J.Shelton, J.Zhu, D.Nepomuceno, J.Wu, J.Chen, F.Kamme, M.Seierstad, M.D.Hack, R.A.Bathgate, M.A.Hossain, J.D.Wade, J.Atack, T.W.Lovenberg, and C.Liu (2007).
R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization.
  J Biol Chem, 282, 25425-25435.  
17316095 C.Poulsen, L.Langkjaer, and C.Worsøe (2007).
Precipitation of insulin aspart and insulin glulisine products used for continuous subcutaneous insulin infusion.
  Diabetes Technol Ther, 9, 26-35.  
18093308 M.Norrman, and G.Schluckebier (2007).
Crystallographic characterization of two novel crystal forms of human insulin induced by chaotropic agents and a shift in pH.
  BMC Struct Biol, 7, 83.
PDB codes: 2oly 2olz 2om0 2om1
17316105 R.H.Becker (2007).
Insulin glulisine complementing basal insulins: a review of structure and activity.
  Diabetes Technol Ther, 9, 109-121.  
12645006 O.V.Moroz, G.G.Dodson, K.S.Wilson, E.Lukanidin, and I.B.Bronstein (2003).
Multiple structural states of S100A12: A key to its functional diversity.
  Microsc Res Tech, 60, 581-592.  
11856825 O.V.Moroz, A.A.Antson, E.J.Dodson, H.J.Burrell, S.J.Grist, R.M.Lloyd, N.J.Maitland, G.G.Dodson, K.S.Wilson, E.Lukanidin, and I.B.Bronstein (2002).
The structure of S100A12 in a hexameric form and its proposed role in receptor signalling.
  Acta Crystallogr D Biol Crystallogr, 58, 407-413.
PDB code: 1gqm
11923277 T.Kjeldsen, S.Ludvigsen, I.Diers, P.Balschmidt, A.R.Sorensen, and N.C.Kaarsholm (2002).
Engineering-enhanced protein secretory expression in yeast with application to insulin.
  J Biol Chem, 277, 18245-18248.  
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
11092919 G.D.Smith, E.Ciszak, L.A.Magrum, W.A.Pangborn, and R.H.Blessing (2000).
R6 hexameric insulin complexed with m-cresol or resorcinol.
  Acta Crystallogr D Biol Crystallogr, 56, 1541-1548.
PDB codes: 1ev3 1ev6 1evr
10449742 C.Clementi, P.Carloni, and A.Maritan (1999).
Protein design is a key factor for subunit-subunit association.
  Proc Natl Acad Sci U S A, 96, 9616-9621.  
10397800 H.Berchtold, and R.Hilgenfeld (1999).
Binding of phenol to R6 insulin hexamers.
  Biopolymers, 51, 165-172.  
10837704 J.Brange, and A.Vølund (1999).
Insulin analogs with improved pharmacokinetic profiles.
  Adv Drug Deliv Rev, 35, 307-335.  
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.