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PDBsum entry 1rwe

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protein ligands metals Protein-protein interface(s) links
Hormone/growth factor PDB id
1rwe
Jmol
Contents
Protein chains
21 a.a.
30 a.a. *
Ligands
IPH
Metals
_CL ×2
_ZN ×2
Waters ×136
* Residue conservation analysis
PDB id:
1rwe
Name: Hormone/growth factor
Title: Enhancing the activity of insulin at receptor edge: crystal and photo-cross-linking of a8 analogues
Structure: Insulin. Chain: a, c. Fragment: insulin a chain. Engineered: yes. Mutation: yes. Insulin. Chain: b, d. Fragment: insulin b chain. Engineered: yes
Source: Synthetic: yes. Synthetic: yes
Biol. unit: Dodecamer (from PDB file)
Resolution:
1.80Å     R-factor:   0.189     R-free:   0.245
Authors: Z.Wan,B.Xu,Y.C.Chu,B.Li,S.H.Nakagawa,Y.Qu,S.Q.Hu,P.G.Katsoya M.A.Weiss
Key ref:
Z.Wan et al. (2004). Enhancing the activity of insulin at the receptor interface: crystal structure and photo-cross-linking of A8 analogues. Biochemistry, 43, 16119-16133. PubMed id: 15610006 DOI: 10.1021/bi048223f
Date:
16-Dec-03     Release date:   15-Feb-05    
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)

 

 
DOI no: 10.1021/bi048223f Biochemistry 43:16119-16133 (2004)
PubMed id: 15610006  
 
 
Enhancing the activity of insulin at the receptor interface: crystal structure and photo-cross-linking of A8 analogues.
Z.Wan, B.Xu, K.Huang, Y.C.Chu, B.Li, S.H.Nakagawa, Y.Qu, S.Q.Hu, P.G.Katsoyannis, M.A.Weiss.
 
  ABSTRACT  
 
The receptor-binding surface of insulin is broadly conserved, reflecting its evolutionary optimization. Neighboring positions nevertheless offer an opportunity to enhance activity, through either transmitted structural changes or introduction of novel contacts. Nonconserved residue A8 is of particular interest as Thr(A8) --> His substitution (a species variant in birds and fish) augments the potency of human insulin. Diverse A8 substitutions are well tolerated, suggesting that the hormone-receptor interface is not tightly packed at this site. To resolve whether enhanced activity is directly or indirectly mediated by the variant A8 side chain, we have determined the crystal structure of His(A8)-insulin and investigated the photo-cross-linking properties of an A8 analogue containing p-azidophenylalanine. The structure, characterized as a T(3)R(3)(f) zinc hexamer at 1.8 A resolution, is essentially identical to that of native insulin. The photoactivatable analogue exhibits efficient cross-linking to the insulin receptor. The site of cross-linking lies within a 14 kDa C-terminal domain of the alpha-subunit. This contact, to our knowledge the first to be demonstrated from the A chain, is inconsistent with a recent model of the hormone-receptor complex derived from electron microscopy. Optimizing the binding interaction of a nonconserved side chain on the surface of insulin may thus enhance its activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19321435 B.Xu, K.Huang, Y.C.Chu, S.Q.Hu, S.Nakagawa, S.Wang, R.Y.Wang, J.Whittaker, P.G.Katsoyannis, and M.A.Weiss (2009).
Decoding the Cryptic Active Conformation of a Protein by Synthetic Photoscanning: INSULIN INSERTS A DETACHABLE ARM BETWEEN RECEPTOR DOMAINS.
  J Biol Chem, 284, 14597-14608.  
19274663 C.W.Ward, and M.C.Lawrence (2009).
Ligand-induced activation of the insulin receptor: a multi-step process involving structural changes in both the ligand and the receptor.
  Bioessays, 31, 422-434.  
19618407 G.Le Flem, J.Pecher, V.Le Flem-Bonhomme, A.Withdrawn, J.Rochette, J.P.Pujol, and P.Bogdanowicz (2009).
Human insulin A-chain peptide analog(s) with in vitro biological activity.
  Cell Biochem Funct, 27, 370-377.  
19850922 M.Liu, Z.L.Wan, Y.C.Chu, H.Aladdin, B.Klaproth, M.Choquette, Q.X.Hua, R.B.Mackin, J.S.Rao, P.De Meyts, P.G.Katsoyannis, P.Arvan, and M.A.Weiss (2009).
Crystal structure of a "nonfoldable" insulin: impaired folding efficiency despite native activity.
  J Biol Chem, 284, 35259-35272.
PDB code: 3gky
19773552 M.Zhao, Z.L.Wan, L.Whittaker, B.Xu, N.B.Phillips, P.G.Katsoyannis, F.Ismail-Beigi, J.Whittaker, and M.A.Weiss (2009).
Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications.
  J Biol Chem, 284, 32178-32187.
PDB code: 3fq9
18048361 L.Gauguin, B.Klaproth, W.Sajid, A.S.Andersen, K.A.McNeil, B.E.Forbes, and P.De Meyts (2008).
Structural Basis for the Lower Affinity of the Insulin-like Growth Factors for the Insulin Receptor.
  J Biol Chem, 283, 2604-2613.  
17280834 C.W.Ward, M.C.Lawrence, V.A.Streltsov, T.E.Adams, and N.M.McKern (2007).
The insulin and EGF receptor structures: new insights into ligand-induced receptor activation.
  Trends Biochem Sci, 32, 129-137.  
17410596 J.P.Mayer, F.Zhang, and R.D.DiMarchi (2007).
Insulin structure and function.
  Biopolymers, 88, 687-713.  
17884811 K.Huang, S.J.Chan, Q.X.Hua, Y.C.Chu, R.Y.Wang, B.Klaproth, W.Jia, J.Whittaker, P.De Meyts, S.H.Nakagawa, D.F.Steiner, P.G.Katsoyannis, and M.A.Weiss (2007).
The A-chain of insulin contacts the insert domain of the insulin receptor. Photo-cross-linking and mutagenesis of a diabetes-related crevice.
  J Biol Chem, 282, 35337-35349.
PDB codes: 2jum 2juu 2juv
17851071 M.C.Lawrence, N.M.McKern, and C.W.Ward (2007).
Insulin receptor structure and its implications for the IGF-1 receptor.
  Curr Opin Struct Biol, 17, 699-705.  
17716170 M.Koch, F.F.Schmid, V.Zoete, and M.Meuwly (2006).
Insulin: a model system for nanomedicine?
  Nanomed, 1, 373-378.  
16894147 M.Lou, T.P.Garrett, N.M.McKern, P.A.Hoyne, V.C.Epa, J.D.Bentley, G.O.Lovrecz, L.J.Cosgrove, M.J.Frenkel, and C.W.Ward (2006).
The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity.
  Proc Natl Acad Sci U S A, 103, 12429-12434.
PDB code: 2hr7
15936977 A.Denley, L.J.Cosgrove, G.W.Booker, J.C.Wallace, and B.E.Forbes (2005).
Molecular interactions of the IGF system.
  Cytokine Growth Factor Rev, 16, 421-439.  
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 code is shown on the right.