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PDBsum entry 2hw9

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protein ligands Protein-protein interface(s) links
Hormone/growth factor PDB id
2hw9
Jmol
Contents
Protein chains
141 a.a. *
Ligands
SO4 ×2
FMT ×3
Waters ×243
* Residue conservation analysis
PDB id:
2hw9
Name: Hormone/growth factor
Title: Crystal structure of lys12cys/cys117val mutant of human acidic fibroblast growth factor at 1.60 angstrom resolution.
Structure: Heparin-binding growth factor 1. Chain: a, b. Synonym: hbgf-1, acidic fibroblast growth factor, afgf, beta-endothelial cell growth factor, ecgf-beta. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: fgf1, fgfa. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
1.60Å     R-factor:   0.202     R-free:   0.221
Authors: V.K.Dubey,J.Lee,T.Somasundaram,M.Blaber
Key ref:
V.K.Dubey et al. (2007). Spackling the crack: stabilizing human fibroblast growth factor-1 by targeting the N and C terminus beta-strand interactions. J Mol Biol, 371, 256-268. PubMed id: 17570396 DOI: 10.1016/j.jmb.2007.05.065
Date:
01-Aug-06     Release date:   12-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P05230  (FGF1_HUMAN) -  Fibroblast growth factor 1
Seq:
Struc:
155 a.a.
141 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   8 terms 
  Biological process     Fc-epsilon receptor signaling pathway   26 terms 
  Biochemical function     S100 protein binding     7 terms  

 

 
DOI no: 10.1016/j.jmb.2007.05.065 J Mol Biol 371:256-268 (2007)
PubMed id: 17570396  
 
 
Spackling the crack: stabilizing human fibroblast growth factor-1 by targeting the N and C terminus beta-strand interactions.
V.K.Dubey, J.Lee, T.Somasundaram, S.Blaber, M.Blaber.
 
  ABSTRACT  
 
The beta-trefoil protein human fibroblast growth factor-1 (FGF-1) is made up of a six-stranded antiparallel beta-barrel closed off on one end by three beta-hairpins, thus exhibiting a 3-fold axis of structural symmetry. The N and C terminus beta-strands hydrogen bond to each other and their interaction is postulated from both NMR and X-ray structure data to be important in folding and stability. Specific mutations within the adjacent N and C terminus beta-strands of FGF-1 are shown to provide a substantial increase in stability. This increase is largely correlated with an increased folding rate constant, and with a smaller but significant decrease in the unfolding rate constant. A series of stabilizing mutations are subsequently combined and result in a doubling of the DeltaG value of unfolding. When taken in the context of previous studies of stabilizing mutations, the results indicate that although FGF-1 is known for generally poor thermal stability, the beta-trefoil architecture appears capable of substantial thermal stability. Targeting stabilizing mutations within the N and C terminus beta-strand interactions of a beta-barrel architecture may be a generally useful approach to increase protein stability. Such stabilized mutations of FGF-1 are shown to exhibit significant increases in effective mitogenic potency, and may prove useful as "second generation" forms of FGF-1 for application in angiogenic therapy.
 
  Selected figure(s)  
 
Figure 1.
Figure 4.
Figure 4. (a) Relaxed stereo diagram of the local structure of FGF-1 in the region of positions Lys12 and Pro134 and including the hydrogen-bonding network. Also shown are two small solvent excluded cavities, detectable using a 1.2 Å radius probe. (b) Relaxed stereo diagram showing an overlay of the Lys12Cys, Lys12Thr, and Lys12Val X-ray structures with WT* (dark grey) in the region of the mutation site. The solvent excluded cavity adjacent to position 12 is filled with each mutation. (c) Relaxed stereo diagram showing an overlay of the Pro134Cys X-ray structure with WT* (dark grey) in the region of the mutation site. The solvent excluded cavity adjacent to position 12 is no longer detectable due to the rotation of the Leu14 side-chain. (d) Relaxed stereo diagram showing an overlay of the Lys12Val/Asn95Val X-ray structure with WT* (dark grey) in the region of the mutation site. The solvent excluded cavities adjacent to position 12 and 134 are no longer detectable due to the position 12 mutation and the adjustment of Pro134 in response to the position 95 mutation.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 371, 256-268) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21173271 J.Lee, and M.Blaber (2011).
Experimental support for the evolution of symmetric protein architecture from a simple peptide motif.
  Proc Natl Acad Sci U S A, 108, 126-130.
PDB codes: 3o49 3o4a 3o4b 3o4c 3o4d 3ogf 3ol0
21315087 J.Lee, S.I.Blaber, V.K.Dubey, and M.Blaber (2011).
A polypeptide "building block" for the β-trefoil fold identified by "top-down symmetric deconstruction".
  J Mol Biol, 407, 744-763.
PDB code: 3o3q
19247306 A.Beenken, and M.Mohammadi (2009).
The FGF family: biology, pathophysiology and therapy.
  Nat Rev Drug Discov, 8, 235-253.  
18710495 M.Asada, E.Honda, and T.Imamura (2008).
Biologically active fibroblast growth factor 1 tagged with various epitopes.
  BMC Res Notes, 1, 42.  
18650393 S.Gosavi, P.C.Whitford, P.A.Jennings, and J.N.Onuchic (2008).
Extracting function from a beta-trefoil folding motif.
  Proc Natl Acad Sci U S A, 105, 10384-10389.  
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