spacer
spacer

PDBsum entry 1kf9

Go to PDB code: 
protein Protein-protein interface(s) links
Hormone/growth factor PDB id
1kf9
Jmol
Contents
Protein chains
160 a.a. *
193 a.a. *
175 a.a. *
Waters ×74
* Residue conservation analysis
PDB id:
1kf9
Name: Hormone/growth factor
Title: Phage display derived variant of human growth hormone complexed with two copies of the extracellular domain of its receptor
Structure: Phage display derived variant human growth hormone. Chain: a, d. Engineered: yes. Extracellular domain human growth hormone receptor (1-238). Chain: b, c, e, f. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Biol. unit: Trimer (from PQS)
Resolution:
2.60Å     R-factor:   0.234     R-free:   0.326
Authors: C.A.Schiffer,M.Ultsch,S.Walsh,W.Somers,A.M.De Vos, A.A.Kossiakoff
Key ref:
C.Schiffer et al. (2002). Structure of a phage display-derived variant of human growth hormone complexed to two copies of the extracellular domain of its receptor: evidence for strong structural coupling between receptor binding sites. J Mol Biol, 316, 277-289. PubMed id: 11851338 DOI: 10.1006/jmbi.2001.5348
Date:
19-Nov-01     Release date:   20-Nov-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01241  (SOMA_HUMAN) -  Somatotropin
Seq:
Struc:
217 a.a.
160 a.a.*
Protein chains
Pfam   ArchSchema ?
P10912  (GHR_HUMAN) -  Growth hormone receptor
Seq:
Struc:
 
Seq:
Struc:
638 a.a.
193 a.a.
Protein chain
Pfam   ArchSchema ?
P10912  (GHR_HUMAN) -  Growth hormone receptor
Seq:
Struc:
 
Seq:
Struc:
638 a.a.
175 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 15 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   3 terms 
  Biological process     bone maturation   16 terms 
  Biochemical function     protein binding     7 terms  

 

 
DOI no: 10.1006/jmbi.2001.5348 J Mol Biol 316:277-289 (2002)
PubMed id: 11851338  
 
 
Structure of a phage display-derived variant of human growth hormone complexed to two copies of the extracellular domain of its receptor: evidence for strong structural coupling between receptor binding sites.
C.Schiffer, M.Ultsch, S.Walsh, W.Somers, A.M.de Vos, A.Kossiakoff.
 
  ABSTRACT  
 
The structure of the ternary complex between the phage display- optimized, high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6 A resolution. There are widespread and significant structural differences compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v)) contains 15 Site 1 mutations and binds>10(2) tighter to the hGHR ECD (hGH(R1)) at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1 interface is somewhat smaller and 20% more hydrophobic compared to the wild-type (wt) counterpart. Of the ten hormone-receptor H-bonds in the site, only one is the same as in the wt complex. Additionally, several regions of hGH(v) structure move up to 9A in forming the interface. The contacts between the C-terminal domains of two receptor ECDs (hGH(R1)- hGH(R2)) are conserved; however, the large changes in Site 1 appear to cause global changes in the domains of hGH(R1) that affect the hGH(v)-hGH(R2) interface indirectly. This coupling is manifested by large changes in the conformation of groups participating in the Site 2 interaction and results in a structure for the site that is reorganized extensively. The hGH(v)- hGH(R2) interface contains seven H-bonds, only one of which is found in the wt complex. Several groups on hGH(v) and hGH(R2) undergo conformational changes of up to 8 A. Asp116 of hGH(v) plays a central role in the reorganization of Site 2 by forming two new H-bonds to the side-chains of Trp104(R2) and Trp169(R2), which are the key binding determinants of the receptor. The fact that a different binding solution is possible for Site 2, where there were no mutations or binding selection pressures, indicates that the structural elements found in these molecules possess an inherent functional plasticity that enables them to bind to a wide variety of binding surfaces.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. Conformational changes in mini-helix residues (42, 45, 46) comparing the free hGH[v] molecule (top) and the bound hGH[v] to hGH[R1] (bottom). H-bonding interactions with receptor groups are shown for the bound form.
Figure 7.
Figure 7. Stereo drawing comparing the region around Trp169[R2] in Site 2. The wt complex residues are colored in green (top). The hGH[v] complex residues are shown in yellow (bottom). Hormone residues are labeled in black and receptor residues in red. Arrows point to the carbonyl oxygen atom of the peptide bond (169) that flips the conformation of the Trp169[R2] side-chain.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 316, 277-289) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
19081054 E.L.Humphris, and T.Kortemme (2008).
Prediction of protein-protein interface sequence diversity using flexible backbone computational protein design.
  Structure, 16, 1777-1788.  
18508672 K.Kadaveru, J.Vyas, and M.R.Schiller (2008).
Viral infection and human disease--insights from minimotifs.
  Front Biosci, 13, 6455-6471.  
17471459 A.B.Chowdry, K.A.Reynolds, M.S.Hanes, M.Voorhies, N.Pokala, and T.M.Handel (2007).
An object-oriented library for computational protein design.
  J Comput Chem, 28, 2378-2388.  
16762925 G.Pál, J.L.Kouadio, D.R.Artis, A.A.Kossiakoff, and S.S.Sidhu (2006).
Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning.
  J Biol Chem, 281, 22378-22385.  
16131663 G.Pál, S.Y.Fong, A.A.Kossiakoff, and S.S.Sidhu (2005).
Alternative views of functional protein binding epitopes obtained by combinatorial shotgun scanning mutagenesis.
  Protein Sci, 14, 2405-2413.  
15857837 J.L.Kouadio, J.R.Horn, G.Pal, and A.A.Kossiakoff (2005).
Shotgun alanine scanning shows that growth hormone can bind productively to its receptor through a drastically minimized interface.
  J Biol Chem, 280, 25524-25532.  
15563602 S.T.Walsh, J.E.Sylvester, and A.A.Kossiakoff (2004).
The high- and low-affinity receptor binding sites of growth hormone are allosterically coupled.
  Proc Natl Acad Sci U S A, 101, 17078-17083.  
15297460 Y.Wan, A.McDevitt, B.Shen, M.L.Smythe, and M.J.Waters (2004).
Increased site 1 affinity improves biopotency of porcine growth hormone. Evidence against diffusion dependent receptor dimerization.
  J Biol Chem, 279, 44775-44784.  
12604795 M.Högbom, M.Eklund, P.A.Nygren, and P.Nordlund (2003).
Structural basis for recognition by an in vitro evolved affibody.
  Proc Natl Acad Sci U S A, 100, 3191-3196.
PDB code: 1lp1
12930995 S.T.Walsh, L.M.Jevitts, J.E.Sylvester, and A.A.Kossiakoff (2003).
Site2 binding energetics of the regulatory step of growth hormone-induced receptor homodimerization.
  Protein Sci, 12, 1960-1970.  
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.