6AVR

Human alpha-V beta-3 Integrin (intermediate conformation) in complex with the therapeutic antibody LM609


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 35.0 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human alpha V beta 3 Integrin via Steric Hindrance.

Borst, A.J.James, Z.M.Zagotta, W.N.Ginsberg, M.Rey, F.A.DiMaio, F.Backovic, M.Veesler, D.

(2017) Structure 25: 1732-1739.e5

  • DOI: https://doi.org/10.1016/j.str.2017.09.007
  • Primary Citation of Related Structures:  
    5OPY, 6AVQ, 6AVR, 6AVU

  • PubMed Abstract: 

    The LM609 antibody specifically recognizes α V β 3 integrin and inhibits angiogenesis, bone resorption, and viral infections in an arginine-glycine-aspartate-independent manner. LM609 entered phase II clinical trials for the treatment of several cancers and was also used for α V β 3 -targeted radioimmunotherapy. To elucidate the mechanisms of recognition and inhibition of α V β 3 integrin, we solved the structure of the LM609 antigen-binding fragment by X-ray crystallography and determined its binding affinity for α V β 3 . Using single-particle electron microscopy, we show that LM609 binds at the interface between the β-propeller domain of the α V chain and the βI domain of the β 3 chain, near the RGD-binding site, of all observed integrin conformational states. Integrating these data with fluorescence size-exclusion chromatography, we demonstrate that LM609 sterically hinders access of large ligands to the RGD-binding pocket, without obstructing it. This work provides a structural framework to expedite future efforts utilizing LM609 as a diagnostic or therapeutic tool.


  • Organizational Affiliation

    Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin alpha-V957Homo sapiensMutation(s): 0 
Gene Names: ITGAVMSK8VNRAVTNR
UniProt & NIH Common Fund Data Resources
Find proteins for P06756 (Homo sapiens)
Explore P06756 
Go to UniProtKB:  P06756
PHAROS:  P06756
GTEx:  ENSG00000138448 
Entity Groups  
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UniProt GroupP06756
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin beta-3692Homo sapiensMutation(s): 0 
Gene Names: ITGB3GP3A
UniProt & NIH Common Fund Data Resources
Find proteins for P05106 (Homo sapiens)
Explore P05106 
Go to UniProtKB:  P05106
PHAROS:  P05106
GTEx:  ENSG00000259207 
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UniProt GroupP05106
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Fab LM609 heavy chainC [auth H]257Mus musculusMutation(s): 0 
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Fab LM609 light chainD [auth L]214Mus musculusMutation(s): 0 
Entity Groups  
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 35.0 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 
EM Software:
TaskSoftware PackageVersion
MODEL REFINEMENTRosetta

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-01
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Database references
  • Version 1.2: 2018-07-18
    Changes: Data collection
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references