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PDBsum entry 1k3m
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protein Protein-protein interface(s) links
Hormone/growth factor PDB id
1k3m

 

 

 

 

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Contents
Protein chains
21 a.a.
30 a.a. *
* Residue conservation analysis
PDB id:
1k3m
Name: Hormone/growth factor
Title: Nmr structure of human insulin mutant ile-a2-ala, his-b10-asp, pro- b28-lys, lys-b29-pro, 15 structures
Structure: Insulin. Chain: a. Fragment: insulin a chain (residues 90-110). Engineered: yes. Mutation: yes. Insulin. Chain: b. Fragment: insulin b chain (residues 25-54). Engineered: yes.
Source: Synthetic: yes. Other_details: the peptide was chemically synthesized. The sequence of the peptide is naturally found in homo sapiens (human).. Of the peptide is naturally found in homo sapiens (human).
NMR struc: 15 models
Authors: B.Xu,Q.-X.Hua,S.H.Nakagawa,W.Jia,Y.-C.Chu,P.G.Katsoyannis,M.A.Weiss
Key ref: B.Xu et al. (2002). A cavity-forming mutation in insulin induces segmental unfolding of a surrounding alpha-helix. Protein Sci, 11, 104-116. PubMed id: 11742127
Date:
03-Oct-01     Release date:   17-Oct-01    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin from Homo sapiens
Seq:
Struc: 		110 a.a.
21 a.a.*
Protein chain
Pfam   ArchSchema ?
P01308  (INS_HUMAN) -  Insulin from Homo sapiens
Seq:
Struc: 		110 a.a.
30 a.a.*
Key:    PfamA domain  Secondary structure
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 

 
Protein Sci 11:104-116 (2002)
PubMed id: 11742127  
 
 
A cavity-forming mutation in insulin induces segmental unfolding of a surrounding alpha-helix.
B.Xu, Q.X.Hua, S.H.Nakagawa, W.Jia, Y.C.Chu, P.G.Katsoyannis, M.A.Weiss.
 
  ABSTRACT  
 
To investigate the cooperativity of insulin's structure, a cavity-forming substitution was introduced within the hydrophobic core of an engineered monomer. The substitution, Ile(A2)-->Ala in the A1-A8 alpha-helix, does not impair disulfide pairing between chains. In accord with past studies of cavity-forming mutations in globular proteins, a decrement was observed in thermodynamic stability (DeltaDeltaG(u) 0.4-1.2 kcal/mole). Unexpectedly, CD studies indicate an attenuated alpha-helix content, which is assigned by NMR spectroscopy to selective destabilization of the A1-A8 segment. The analog's solution structure is otherwise similar to that of native insulin, including the B chain's supersecondary structure and a major portion of the hydrophobic core. Our results show that (1) a cavity-forming mutation in a globular protein can lead to segmental unfolding, (2) tertiary packing of Ile(A2), a residue of low helical propensity, stabilizes the A1-A8 alpha-helix, and (3) folding of this segment is not required for native disulfide pairing or overall structure. We discuss these results in relation to a hierarchical pathway of protein folding and misfolding. The Ala(A2) analog's low biological activity (0.5% relative to the parent monomer) highlights the importance of the A1-A8 alpha-helix in receptor recognition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19959476 Y.Sohma, Q.X.Hua, M.Liu, N.B.Phillips, S.Q.Hu, J.Whittaker, L.J.Whittaker, A.Ng, C.T.Roberts, P.Arvan, S.B.Kent, and M.A.Weiss (2010).
Contribution of residue B5 to the folding and function of insulin and IGF-I: constraints and fine-tuning in the evolution of a protein family.
  J Biol Chem, 285, 5040-5055.  
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
19321446 M.Manolopoulou, Q.Guo, E.Malito, A.B.Schilling, and W.J.Tang (2009).
Molecular Basis of Catalytic Chamber-assisted Unfolding and Cleavage of Human Insulin by Human Insulin-degrading Enzyme.
  J Biol Chem, 284, 14177-14188.
PDB codes: 2wby 2wc0
17410596 J.P.Mayer, F.Zhang, and R.D.DiMarchi (2007).
Insulin structure and function.
  Biopolymers, 88, 687-713.  
17523191 M.Bueno, C.J.Camacho, and J.Sancho (2007).
SIMPLE estimate of the free energy change due to aliphatic mutations: superior predictions based on first principles.
  Proteins, 68, 850-862.  
16877708 M.Bueno, L.A.Campos, J.Estrada, and J.Sancho (2006).
Energetics of aliphatic deletions in protein cores.
  Protein Sci, 15, 1858-1872.  
17716170 M.Koch, F.F.Schmid, V.Zoete, and M.Meuwly (2006).
Insulin: a model system for nanomedicine?
  Nanomed, 1, 373-378.  
16981237 V.Zoete, and M.Meuwly (2006).
Importance of individual side chains for the stability of a protein fold: computational alanine scanning of the insulin monomer.
  J Comput Chem, 27, 1843-1857.  
16167086 A.M.Kennedy, M.Inada, S.M.Krane, P.T.Christie, B.Harding, C.López-Otín, L.M.Sánchez, A.A.Pannett, A.Dearlove, C.Hartley, M.H.Byrne, A.A.Reed, M.A.Nesbit, M.P.Whyte, and R.V.Thakker (2005).
MMP13 mutation causes spondyloepimetaphyseal dysplasia, Missouri type (SEMD(MO).
  J Clin Invest, 115, 2832-2842.  
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.  
14596591 Z.L.Wan, B.Xu, Y.C.Chu, P.G.Katsoyannis, and M.A.Weiss (2003).
Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding.
  Biochemistry, 42, 12770-12783.
PDB codes: 1lw8 1pc1 1q4v
12208966 S.H.Xiang, P.D.Kwong, R.Gupta, C.D.Rizzuto, D.J.Casper, R.Wyatt, L.Wang, W.A.Hendrickson, M.L.Doyle, and J.Sodroski (2002).
Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein.
  J Virol, 76, 9888-9899.  
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.

 

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