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Immune system PDB id
1cqp
Jmol
Contents
Protein chains
182 a.a. *
Ligands
803 ×2
Metals
_MG ×2
Waters ×86
* Residue conservation analysis
PDB id:
1cqp
Name: Immune system
Title: Crystal structure analysis of the complex lfa-1 (cd11a) i- domain / lovastatin at 2.6 a resolution
Structure: Antigen cd11a (p180). Chain: a, b. Fragment: i-domain, residues 153-334. Synonym: integrin alpha l, lymphocyte function-associated antigen 1. Alpha polypeptide. Engineered: yes. Other_details: complexed with lovastatin which occurs naturally in fungi
Source: Homo sapiens. Human. Organism_taxid: 9606
Biol. unit: Dimer (from PQS)
Resolution:
2.60Å     R-factor:   0.190     R-free:   0.257
Authors: J.Kallen,K.Welzenbach,P.Ramage,D.Geyl,R.Kriwacki,G.Legge, S.Cottens,G.Weitz-Schmidt,U.Hommel
Key ref:
J.Kallen et al. (1999). Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol, 292, 1-9. PubMed id: 10493852 DOI: 10.1006/jmbi.1999.3047
Date:
10-Aug-99     Release date:   07-Aug-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P20701  (ITAL_HUMAN) -  Integrin alpha-L
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1170 a.a.
182 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
DOI no: 10.1006/jmbi.1999.3047 J Mol Biol 292:1-9 (1999)
PubMed id: 10493852  
 
 
Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain.
J.Kallen, K.Welzenbach, P.Ramage, D.Geyl, R.Kriwacki, G.Legge, S.Cottens, G.Weitz-Schmidt, U.Hommel.
 
  ABSTRACT  
 
The lymphocyte function-associated antigen (LFA-1) belongs to the family of beta2-integrins and plays an important role in T-cell activation and leukocyte migration to sites of inflammation. We report here that lovastatin, a drug clinically used for lowering cholesterol levels, inhibits the interaction of human LFA-1 with its counter-receptor intercellular adhesion molecule-1. Using nuclear magnetic resonance spectroscopy and X-ray crystallography we show that the inhibitor binds to a highly conserved domain of the LFA-1 alpha-chain called the I-domain. The first three-dimensional structure of an integrin inhibitor bound to its receptor reveals atomic details for a hitherto unknown mode of LFA-1 inhibition. It also sheds light into possible mechanisms of LFA-1 mediated signalling and will support the design of novel anti-adhesive and immunosuppressive drugs.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. (a) Structure of the I-domain/lovastatin complex. A trace through the position of backbone nitrogen atoms is shown in black. The magnitude of the chemical shift changes observed in the NMR experiments is mapped on the three-dimensional structure of the aL I-domain/lovastatin complex. The size of the spheres representing backbone nitrogen atoms (cyan) is proportional to the magnitude of chemical shift displacements (1 Å/ppm). Lovastatin is shown in green and the magnesium ion of the MIDAS motif in magenta with a sphere radius of 1 Å. The N and C-termini are indicated by N and C, respectively. (b) A close-up of the lovastatin binding pocket is shown. Residues within the lovastatin binding pocket are indicated by their residue number. The final 2 F[o] -F[c]electron density contoured at one standard deviation above the mean (blue) shows the lactone moiety of lovastatin to be less well defined relative to the core of the ligand. This may reflect the susceptibility of the ligand to hydrolysis under the crystallization conditions. Carbon atoms of the I-domain and lovastatin are coloured yellow and cyan, respectively. Carbon atoms of residues from the second aL I-domain complex within the asymmetric unit are coloured green. 		Figure 5.
Figure 5. (a) Biological context of the lovastatin binding pocket. Lovastatin shown in red binds to a crevice which is close to the IdeA epitope, residues 128-129 in gold [Champe et al 1995] and a region implicated in LFA-1 activation, residues 223-233 in green [McDowall et al 1998]. It is also close to a sequence of the aL I-domain linked to treatment resistant Lyme disease, residues 307-309 in yellow [Gross et al 1998]. Only residues for which clear electron density was observed are indicated. The ribbon is drawn though the C^apositons of the I-domain and a sphere (magenta) indicates the location of the magnesium ion in the MIDAS motif. (b) Conformational variability of the lovastatin binding pocket. Superposition of the metal-free unliganded structure of aL I-domain in yellow ([Qu and Leahy 1996]; PDB entry 1zon) with that of the aL I-domain/lovastatin complex in blue. The lovastatin binding pocket is not present in the former structure due to the packing of helix a7 onto the central b-sheet. Lovastatin is shown in red and the magnesium ion occupying the MIDAS motif in the lovastatin complex in magenta. The N and C termini are indicated by N and C, respectively.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 292, 1-9) copyright 1999.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21385989 K.Yuki, S.G.Soriano, and M.Shimaoka (2011).
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  Protein Sci, 15, 290-303.  
17023419 W.Yang, C.V.Carman, M.Kim, A.Salas, M.Shimaoka, and T.A.Springer (2006).
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16212526 C.Gilbert, M.Bergeron, S.Méthot, J.F.Giguère, and M.J.Tremblay (2005).
Statins could be used to control replication of some viruses, including HIV-1.
  Viral Immunol, 18, 474-489.  
15954154 H.Yin, and A.D.Hamilton (2005).
Strategies for targeting protein-protein interactions with synthetic agents.
  Angew Chem Int Ed Engl, 44, 4130-4163.  
15856040 J.I.Cohen (2005).
HMG CoA reductase inhibitors (statins) to treat Epstein-Barr virus-driven lymphoma.
  Br J Cancer, 92, 1593-1598.  
16212500 M.A.Arnaout, B.Mahalingam, and J.P.Xiong (2005).
Integrin structure, allostery, and bidirectional signaling.
  Annu Rev Cell Dev Biol, 21, 381-410.  
15955822 M.R.Sarantos, S.Raychaudhuri, A.F.Lum, D.E.Staunton, and S.I.Simon (2005).
Leukocyte function-associated antigen 1-mediated adhesion stability is dynamically regulated through affinity and valency during bond formation with intercellular adhesion molecule-1.
  J Biol Chem, 280, 28290-28298.  
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[Statins for treatment of CNS diseases Status report from research and clinical practice.]
  Nervenarzt, 76, 426-437.  
16168274 V.Fuster, P.R.Moreno, Z.A.Fayad, R.Corti, and J.J.Badimon (2005).
Atherothrombosis and high-risk plaque: part I: evolving concepts.
  J Am Coll Cardiol, 46, 937-954.  
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  Immunity, 20, 393-406.  
15304496 G.Weitz-Schmidt, K.Welzenbach, J.Dawson, and J.Kallen (2004).
Improved lymphocyte function-associated antigen-1 (LFA-1) inhibition by statin derivatives: molecular basis determined by x-ray analysis and monitoring of LFA-1 conformational changes in vitro and ex vivo.
  J Biol Chem, 279, 46764-46771.
PDB codes: 1xdd 1xdg
15479847 J.F.Giguère, and M.J.Tremblay (2004).
Statin compounds reduce human immunodeficiency virus type 1 replication by preventing the interaction between virion-associated host intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1.
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  Structure, 12, 2137-2147.  
15060526 M.R.Arkin, and J.A.Wells (2004).
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  Curr Neurol Neurosci Rep, 4, 237-244.  
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Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring.
  Proc Natl Acad Sci U S A, 101, 2906-2911.  
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Activation of integrin beta-subunit I-like domains by one-turn C-terminal alpha-helix deletions.
  Proc Natl Acad Sci U S A, 101, 2333-2338.  
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Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice.
  Br J Pharmacol, 141, 709-716.  
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Jararhagin-derived RKKH peptides induce structural changes in alpha1I domain of human integrin alpha1beta1.
  J Biol Chem, 279, 7962-7970.
PDB codes: 1pt6 1qcy
12871301 J.P.Xiong, T.Stehle, S.L.Goodman, and M.A.Arnaout (2003).
Integrins, cations and ligands: making the connection.
  J Thromb Haemost, 1, 1642-1654.  
12826403 M.J.Humphries, P.A.McEwan, S.J.Barton, P.A.Buckley, J.Bella, and A.P.Mould (2003).
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Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation.
  Cell, 112, 99.
PDB codes: 1mjn 1mq8 1mq9 1mqa
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12970101 M.X.Wan, R.Schramm, D.Klintman, K.Welzenbach, G.Weitz-Schmidt, and H.Thorlacius (2003).
A statin-based inhibitor of lymphocyte function antigen-1 protects against ischemia/reperfusion-induced leukocyte adhesion in the colon.
  Br J Pharmacol, 140, 395-401.  
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Statins as potential therapeutic agents in neuroinflammatory disorders.
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Dynamic regulation of LFA-1 activation and neutrophil arrest on intercellular adhesion molecule 1 (ICAM-1) in shear flow.
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Transition from rolling to firm adhesion is regulated by the conformation of the I domain of the integrin lymphocyte function-associated antigen-1.
  J Biol Chem, 277, 50255-50262.  
12112684 G.B.Legge, G.M.Morris, M.F.Sanner, Y.Takada, A.J.Olson, and F.Grynszpan (2002).
Model of the alphaLbeta2 integrin I-domain/ICAM-1 DI interface suggests that subtle changes in loop orientation determine ligand specificity.
  Proteins, 48, 151-160.
PDB code: 1ij4
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Statins as anti-inflammatory agents.
  Trends Pharmacol Sci, 23, 482-486.  
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Integrin activation and structural rearrangement.
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Activation-induced conformational changes in the I domain region of lymphocyte function-associated antigen 1.
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  Proc Natl Acad Sci U S A, 98, 2387-2392.  
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Lovastatin treatment decreases mononuclear cell infiltration into the CNS of Lewis rats with experimental allergic encephalomyelitis.
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Pleiotropic effects of statins.
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NMR and mutagenesis evidence for an I domain allosteric site that regulates lymphocyte function-associated antigen 1 ligand binding.
  Proc Natl Acad Sci U S A, 97, 5231-5236.  
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