6MSU

Integrin alphaVBeta3 in complex with EETI-II 2.5F


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.11 Å

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This is version 2.1 of the entry. See complete history


Literature

Structural Basis of the Differential Binding of Engineered Knottins to Integrins alpha V beta 3 and alpha 5 beta 1.

Van Agthoven, J.F.Shams, H.Cochran, F.V.Alonso, J.L.Kintzing, J.R.Garakani, K.Adair, B.D.Xiong, J.P.Mofrad, M.R.K.Cochran, J.R.Arnaout, M.A.

(2019) Structure 27: 1443-1451.e6

  • DOI: https://doi.org/10.1016/j.str.2019.06.011
  • Primary Citation of Related Structures:  
    6MSL, 6MSU

  • PubMed Abstract: 

    Targeting both integrins αVβ3 and α5β1 simultaneously appears to be more effective in cancer therapy than targeting each one alone. The structural requirements for bispecific binding of ligand to integrins have not been fully elucidated. RGD-containing knottin 2.5F binds selectively to αVβ3 and α5β1, whereas knottin 2.5D is αVβ3 specific. To elucidate the structural basis of this selectivity, we determined the structures of 2.5F and 2.5D as apo proteins and in complex with αVβ3, and compared their interactions with integrins using molecular dynamics simulations. These studies show that 2.5D engages αVβ3 by an induced fit, but conformational selection of a flexible RGD loop accounts for high-affinity selective binding of 2.5F to both integrins. The contrasting binding of the highly flexible low-affinity linear RGD peptides to multiple integrins suggests that a "Goldilocks zone" of conformational flexibility of the RGD loop in 2.5F underlies its selective binding promiscuity to integrins.


  • Organizational Affiliation

    Leukocyte Biology and Inflammation Program, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Structural Biology Program, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Division of Nephrology/Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin alpha-V967Homo 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  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06756
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin beta-3695Homo 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 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05106
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Engineered EETI-II 2.5F32Ecballium elateriumMutation(s): 0 
UniProt
Find proteins for P12071 (Ecballium elaterium)
Explore P12071 
Go to UniProtKB:  P12071
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12071
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
D, G
4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G81315DD
GlyCosmos:  G81315DD
GlyGen:  G81315DD
Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
E, H, I, K
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 6
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-4)-beta-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F
6N-Glycosylation
Glycosylation Resources
GlyTouCan:  G93290PO
GlyCosmos:  G93290PO
GlyGen:  G93290PO
Entity ID: 7
MoleculeChains Length2D Diagram Glycosylation3D Interactions
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
J, L
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G15407YE
GlyCosmos:  G15407YE
GlyGen:  G15407YE
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
M [auth A],
N [auth A],
O [auth A],
U [auth B],
V [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
P [auth A]
Q [auth A]
R [auth A]
S [auth A]
T [auth A]
P [auth A],
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
W [auth B],
X [auth B],
Y [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
Z [auth C]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.11 Å
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 129.894α = 90
b = 129.894β = 90
c = 305.843γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)United StatesK01DK101628-04

Revision History  (Full details and data files)

  • Version 1.0: 2019-10-23
    Type: Initial release
  • Version 1.1: 2019-11-20
    Changes: Derived calculations
  • Version 1.2: 2019-12-18
    Changes: Author supporting evidence
  • Version 1.3: 2020-02-12
    Changes: Data collection, Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2023-10-11
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary