3HI6

Crystal structure of intermediate affinity I domain of integrin LFA-1 with the Fab fragment of its antibody AL-57


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1.

Zhang, H.Liu, J.H.Yang, W.Springer, T.Shimaoka, M.Wang, J.H.

(2009) Proc Natl Acad Sci U S A 106: 18345-18350

  • DOI: https://doi.org/10.1073/pnas.0909301106
  • Primary Citation of Related Structures:  
    3HI5, 3HI6

  • PubMed Abstract: 

    The activity of integrin LFA-1 (alpha(L)beta(2)) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of alpha(L) chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural features conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules.


  • Organizational Affiliation

    Department of Pediatrics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin alpha-L
A, B
180Homo sapiensMutation(s): 3 
Gene Names: CD11AITGALLFA-1
UniProt & NIH Common Fund Data Resources
Find proteins for P20701 (Homo sapiens)
Explore P20701 
Go to UniProtKB:  P20701
PHAROS:  P20701
GTEx:  ENSG00000005844 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20701
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Heavy chain of Fab fragment of AL-57 against alpha L I domainC [auth H],
E [auth X]
220Homo sapiensMutation(s): 0 
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Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
light chain of Fab fragment of AL-57 against alpha L I domainD [auth L],
F [auth Y]
212Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.173 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 133.78α = 90
b = 133.78β = 90
c = 161.05γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-09-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2021-10-13
    Changes: Database references, Derived calculations