spacer
spacer

PDBsum entry 1axi

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Complex (hormone/receptor) PDB id
1axi
Jmol
Contents
Protein chains
175 a.a. *
191 a.a. *
Ligands
SO4
Waters ×382
* Residue conservation analysis
PDB id:
1axi
Name: Complex (hormone/receptor)
Title: Structural plasticity at the hgh:hghbp interface
Structure: Growth hormone. Chain: a. Synonym: hgh. Engineered: yes. Mutation: yes. Growth hormone receptor. Chain: b. Fragment: extracellular binding domain. Synonym: hghbp.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
2.10Å     R-factor:   0.190     R-free:   0.262
Authors: S.Atwell,M.Ultsch,A.M.De Vos,J.A.Wells
Key ref:
S.Atwell et al. (1997). Structural plasticity in a remodeled protein-protein interface. Science, 278, 1125-1128. PubMed id: 9353194 DOI: 10.1126/science.278.5340.1125
Date:
15-Oct-97     Release date:   28-Jan-98    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P01241  (SOMA_HUMAN) -  Somatotropin
Seq:
Struc:
217 a.a.
175 a.a.*
Protein chain
Pfam   ArchSchema ?
P10912  (GHR_HUMAN) -  Growth hormone receptor
Seq:
Struc:
 
Seq:
Struc:
638 a.a.
191 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 7 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: 10.1126/science.278.5340.1125 Science 278:1125-1128 (1997)
PubMed id: 9353194  
 
 
Structural plasticity in a remodeled protein-protein interface.
S.Atwell, M.Ultsch, A.M.De Vos, J.A.Wells.
 
  ABSTRACT  
 
Remodeling of the interface between human growth hormone (hGH) and the extracellular domain of its receptor was studied by deleting a critical tryptophan residue (at position 104) in the receptor, creating a large cavity, and selecting a pentamutant of hGH by phage display that fills the cavity and largely restores binding affinity. A 2.1 A resolution x-ray structure of the mutant complex showed that the receptor cavity was filled by selected hydrophobic mutations of hGH. Large structural rearrangements occurred in the interface at sites that were distant from the mutations. Such plasticity may be a means for protein-protein interfaces to adapt to mutations as they coevolve.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. Residues in hGHbp (rendered in pink or orange sticks) that contact hGH (in blue space-filling rendition) in the 1:1 wild-type^ complex (A) or the complex between A1-hGH and W104A-hGHbp (B). Local groups where hydrogen bonds are different between the complexes are shown as yellow dashed lines.
Figure 3.
Fig. 3. Two views (A and B) of nonmutated contact residues that change salt bridge partners in the A1-hGH and W104A-hGHbp complex (right) relative to the wild-type complex (left). Hormone^ residues are in blue, and receptor residues are in pink, except for position 104 which is in orange.
 
  The above figures are reprinted by permission from the AAAs: Science (1997, 278, 1125-1128) copyright 1997.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20018744 A.V.Smrcka, N.Kichik, T.Tarragó, M.Burroughs, M.S.Park, N.K.Itoga, H.A.Stern, B.M.Willardson, and E.Giralt (2010).
NMR analysis of G-protein betagamma subunit complexes reveals a dynamic G(alpha)-Gbetagamma subunit interface and multiple protein recognition modes.
  Proc Natl Acad Sci U S A, 107, 639-644.  
21286315 C.P.Bagowski, W.Bruins, and A.J.Te Velthuis (2010).
The nature of protein domain evolution: shaping the interaction network.
  Curr Genomics, 11, 368-376.  
20454584 H.C.Wu, and D.K.Chang (2010).
Peptide-mediated liposomal drug delivery system targeting tumor blood vessels in anticancer therapy.
  J Oncol, 2010, 723798.  
19255244 F.Deák, Y.Xu, W.P.Chang, I.Dulubova, M.Khvotchev, X.Liu, T.C.Südhof, and J.Rizo (2009).
Munc18-1 binding to the neuronal SNARE complex controls synaptic vesicle priming.
  J Cell Biol, 184, 751-764.  
20041191 W.L.Li, and A.G.Rodrigo (2009).
Covariation of branch lengths in phylogenies of functionally related genes.
  PLoS One, 4, e8487.  
18817510 X.Wang, P.Lupardus, S.L.Laporte, and K.C.Garcia (2009).
Structural biology of shared cytokine receptors.
  Annu Rev Immunol, 27, 29-60.  
18537559 A.V.Smrcka, D.M.Lehmann, and A.L.Dessal (2008).
G protein betagamma subunits as targets for small molecule therapeutic development.
  Comb Chem High Throughput Screen, 11, 382-395.  
  19204805 F.M.Codoñer, and M.A.Fares (2008).
Why should we care about molecular coevolution?
  Evol Bioinform Online, 4, 29-38.  
19064911 K.Zhang, M.R.Sawaya, D.S.Eisenberg, and J.C.Liao (2008).
Expanding metabolism for biosynthesis of nonnatural alcohols.
  Proc Natl Acad Sci U S A, 105, 20653-20658.  
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.  
17293401 A.R.Atilgan, D.Turgut, and C.Atilgan (2007).
Screened nonbonded interactions in native proteins manipulate optimal paths for robust residue communication.
  Biophys J, 92, 3052-3062.  
17287826 J.Rudolph (2007).
Inhibiting transient protein-protein interactions: lessons from the Cdc25 protein tyrosine phosphatases.
  Nat Rev Cancer, 7, 202-211.  
17287314 Y.C.Chen, H.N.Huang, C.T.Lin, Y.F.Chen, C.C.King, and H.C.Wu (2007).
Generation and characterization of monoclonal antibodies against dengue virus type 1 for epitope mapping and serological detection by epitope-based peptide antigens.
  Clin Vaccine Immunol, 14, 404-411.  
16937240 A.Canales-Mayordomo, R.Fayos, J.Angulo, R.Ojeda, M.Martín-Pastor, P.M.Nieto, M.Martín-Lomas, R.Lozano, G.Giménez-Gallego, and J.Jiménez-Barbero (2006).
Backbone dynamics of a biologically active human FGF-1 monomer, complexed to a hexasaccharide heparin-analogue, by 15N NMR relaxation methods.
  J Biomol NMR, 35, 225-239.  
15867160 N.Varadarajan, J.Gam, M.J.Olsen, G.Georgiou, and B.L.Iverson (2005).
Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity.
  Proc Natl Acad Sci U S A, 102, 6855-6860.  
15703481 D.Bumbaca, J.E.Littlejohn, H.Nayakanti, D.J.Rigden, M.Y.Galperin, and M.J.Jedrzejas (2004).
Sequence analysis and characterization of a novel fibronectin-binding repeat domain from the surface of Streptococcus pneumoniae.
  OMICS, 8, 341-356.  
15296742 D.Y.Chirgadze, M.Demydchuk, M.Becker, S.Moran, and M.Paoli (2004).
Snapshot of protein structure evolution reveals conservation of functional dimerization through intertwined folding.
  Structure, 12, 1489-1494.
PDB codes: 1u36 1u3j 1u3y 1u3z 1u41 1u42
15653425 E.J.Helmreich (2004).
Structural flexibility of small GTPases. Can it explain their functional versatility?
  Biol Chem, 385, 1121-1136.  
15211515 H.Gohlke, L.A.Kuhn, and D.A.Case (2004).
Change in protein flexibility upon complex formation: analysis of Ras-Raf using molecular dynamics and a molecular framework approach.
  Proteins, 56, 322-337.  
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.  
15289606 S.Y.Park, B.D.Beel, M.I.Simon, A.M.Bilwes, and B.R.Crane (2004).
In different organisms, the mode of interaction between two signaling proteins is not necessarily conserved.
  Proc Natl Acad Sci U S A, 101, 11646-11651.
PDB code: 1u0s
  12707025 D.L.Jaye, F.S.Nolte, L.Mazzucchelli, C.Geigerman, A.Akyildiz, and C.A.Parkos (2003).
Use of real-time polymerase chain reaction to identify cell- and tissue-type-selective peptides by phage display.
  Am J Pathol, 162, 1419-1429.  
14517972 G.M.Verkhivker, D.Bouzida, D.K.Gehlhaar, P.A.Rejto, S.T.Freer, and P.W.Rose (2003).
Computational detection of the binding-site hot spot at the remodeled human growth hormone-receptor interface.
  Proteins, 53, 201-219.  
14527405 M.J.Boulanger, A.J.Bankovich, T.Kortemme, D.Baker, and K.C.Garcia (2003).
Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130.
  Mol Cell, 12, 577-589.
PDB code: 1pvh
12582206 M.R.Arkin, M.Randal, W.L.DeLano, J.Hyde, T.N.Luong, J.D.Oslob, D.R.Raphael, L.Taylor, J.Wang, R.S.McDowell, J.A.Wells, and A.C.Braisted (2003).
Binding of small molecules to an adaptive protein-protein interface.
  Proc Natl Acad Sci U S A, 100, 1603-1608.
PDB codes: 1m47 1m48 1m49 1m4a 1m4b 1m4c
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.  
12021444 A.V.Filikov, R.J.Hayes, P.Luo, D.M.Stark, C.Chan, A.Kundu, and B.I.Dahiyat (2002).
Computational stabilization of human growth hormone.
  Protein Sci, 11, 1452-1461.  
12112677 G.M.Verkhivker, D.Bouzida, D.K.Gehlhaar, P.A.Rejto, S.T.Freer, and P.W.Rose (2002).
Monte Carlo simulations of the peptide recognition at the consensus binding site of the constant fragment of human immunoglobulin G: the energy landscape analysis of a hot spot at the intermolecular interface.
  Proteins, 48, 539-557.  
11807947 L.Jiang, Y.Gao, F.Mao, Z.Liu, and L.Lai (2002).
Potential of mean force for protein-protein interaction studies.
  Proteins, 46, 190-196.  
11839485 O.Lichtarge, and M.E.Sowa (2002).
Evolutionary predictions of binding surfaces and interactions.
  Curr Opin Struct Biol, 12, 21-27.  
11913381 S.Huo, I.Massova, and P.A.Kollman (2002).
Computational alanine scanning of the 1:1 human growth hormone-receptor complex.
  J Comput Chem, 23, 15-27.  
12381794 T.Kortemme, and D.Baker (2002).
A simple physical model for binding energy hot spots in protein-protein complexes.
  Proc Natl Acad Sci U S A, 99, 14116-14121.  
12163066 W.P.Russ, and R.Ranganathan (2002).
Knowledge-based potential functions in protein design.
  Curr Opin Struct Biol, 12, 447-452.  
11425742 H.C.Wu, C.T.Yeh, Y.L.Huang, L.J.Tarn, and C.C.Lung (2001).
Characterization of neutralizing antibodies and identification of neutralizing epitope mimics on the Clostridium botulinum neurotoxin type A.
  Appl Environ Microbiol, 67, 3201-3207.  
11754823 S.Radaev, B.Rostro, A.G.Brooks, M.Colonna, and P.D.Sun (2001).
Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3.
  Immunity, 15, 1039-1049.
PDB code: 1kcg
10903952 E.J.Sundberg, and R.A.Mariuzza (2000).
Luxury accommodations: the expanding role of structural plasticity in protein-protein interactions.
  Structure, 8, R137-R142.  
10704464 H.R.Churchill, P.S.Andersen, E.A.Parke, R.A.Mariuzza, and D.M.Kranz (2000).
Mapping the energy of superantigen Staphylococcus enterotoxin C3 recognition of an alpha/beta T cell receptor using alanine scanning mutagenesis.
  J Exp Med, 191, 835-846.  
11058786 K.J.Kallen, J.Grötzinger, and S.Rose-John (2000).
New perspectives on the design of cytokines and growth factors.
  Trends Biotechnol, 18, 455-461.  
10672010 K.W.Rodenburg, F.Vallée, N.Juge, N.Aghajari, X.Guo, R.Haser, and B.Svensson (2000).
Specific inhibition of barley alpha-amylase 2 by barley alpha-amylase/subtilisin inhibitor depends on charge interactions and can be conferred to isozyme 1 by mutation.
  Eur J Biochem, 267, 1019-1029.  
10852948 T.J.Wandless (2000).
A confederacy of bunches: fundamentals and applications of a self-associating protein.
  Proc Natl Acad Sci U S A, 97, 6921-6923.  
10380930 J.H.Wang, A.Smolyar, K.Tan, J.H.Liu, M.Kim, Z.Y.Sun, G.Wagner, and E.L.Reinherz (1999).
Structure of a heterophilic adhesion complex between the human CD2 and CD58 (LFA-3) counterreceptors.
  Cell, 97, 791-803.
PDB code: 1qa9
  10348859 J.J.Caguiat, A.L.Watson, and A.O.Summers (1999).
Cd(II)-responsive and constitutive mutants implicate a novel domain in MerR.
  J Bacteriol, 181, 3462-3471.  
10631938 K.C.Garcia (1999).
Molecular interactions between extracellular components of the T-cell receptor signaling complex.
  Immunol Rev, 172, 73-85.  
10051576 R.Briesewitz, G.T.Ray, T.J.Wandless, and G.R.Crabtree (1999).
Affinity modulation of small-molecule ligands by borrowing endogenous protein surfaces.
  Proc Natl Acad Sci U S A, 96, 1953-1958.  
10449721 S.Atwell, and J.A.Wells (1999).
Selection for improved subtiligases by phage display.
  Proc Natl Acad Sci U S A, 96, 9497-9502.  
10398368 S.D.Nuttall, M.J.Rousch, R.A.Irving, S.E.Hufton, H.R.Hoogenboom, and P.J.Hudson (1999).
Design and expression of soluble CTLA-4 variable domain as a scaffold for the display of functional polypeptides.
  Proteins, 36, 217-227.  
10611645 S.N.Behncken, and M.J.Waters (1999).
Molecular recognition events involved in the activation of the growth hormone receptor by growth hormone.
  J Mol Recognit, 12, 355-362.  
  9732276 F.W.Whipple, E.F.Hou, and A.Hochschild (1998).
Amino acid-amino acid contacts at the cooperativity interface of the bacteriophage lambda and P22 repressors.
  Genes Dev, 12, 2791-2802.  
9724721 T.Clackson, W.Yang, L.W.Rozamus, M.Hatada, J.F.Amara, C.T.Rollins, L.F.Stevenson, S.R.Magari, S.A.Wood, N.L.Courage, X.Lu, F.Cerasoli, M.Gilman, and D.A.Holt (1998).
Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity.
  Proc Natl Acad Sci U S A, 95, 10437-10442.
PDB code: 1bl4
9729736 T.Clackson (1998).
Redesigning small molecule-protein interfaces.
  Curr Opin Struct Biol, 8, 451-458.  
9649307 W.Dall'Acqua, A.L.Simon, M.G.Mulkerrin, and P.Carter (1998).
Contribution of domain interface residues to the stability of antibody CH3 domain homodimers.
  Biochemistry, 37, 9266-9273.  
9628472 X.Ysern, H.Li, and R.A.Mariuzza (1998).
Imperfect interfaces.
  Nat Struct Biol, 5, 412-414.  
9707600 Y.Ghendler, M.K.Teng, J.H.Liu, T.Witte, J.Liu, K.S.Kim, P.Kern, H.C.Chang, J.H.Wang, and E.L.Reinherz (1998).
Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands.
  Proc Natl Acad Sci U S A, 95, 10061-10066.
PDB code: 1osz
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.