RCSB PDB - 7UCY: Integrin alpha IIB beta3 complex with gantofiban

 7UCY

Integrin alpha IIB beta3 complex with gantofiban


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.221 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MV8Click on this verticalbar to view details

This is version 1.4 of the entry. See complete history


Literature

A general chemical principle for creating closure-stabilizing integrin inhibitors.

Lin, F.Y.Li, J.Xie, Y.Zhu, J.Huong Nguyen, T.T.Zhang, Y.Zhu, J.Springer, T.A.

(2022) Cell 185: 3533-3550.e27

  • DOI: https://doi.org/10.1016/j.cell.2022.08.008
  • Primary Citation of Related Structures:  
    7L8P, 7TCT, 7TD8, 7THO, 7TMZ, 7TPD, 7U60, 7U9F, 7U9V, 7UBR, 7UCY, 7UDG, 7UDH, 7UE0, 7UFH, 7UH8, 7UJE, 7UJK, 7UK9, 7UKO, 7UKP, 7UKT

  • PubMed Abstract: 

    Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.


  • Organizational Affiliation

    Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Integrin alpha-IIb heavy chain
A, C
457Homo sapiensMutation(s): 0 
Gene Names: ITGA2BGP2BITGAB
UniProt & NIH Common Fund Data Resources
Find proteins for P08514 (Homo sapiens)
Explore P08514 
Go to UniProtKB:  P08514
PHAROS:  P08514
GTEx:  ENSG00000005961 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08514
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Isoform Beta-3C of Integrin beta-3
B, D
472Homo 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
Glycosylation
Glycosylation Sites: 3Go to GlyGen: P05106-1
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
10E5 Fab heavy chainE,
G [auth H]
221Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
10E5 Fab light chainF,
H [auth L]
214Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 5
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranoseI [auth G]5N-Glycosylation
Glycosylation Resources
GlyTouCan:  G22768VO
GlyCosmos:  G22768VO
GlyGen:  G22768VO
Entity ID: 6
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranoseJ [auth I],
L [auth K]
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Entity ID: 7
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-glucopyranoseK [auth J]4N-Glycosylation
Glycosylation Resources
GlyTouCan:  G81315DD
GlyCosmos:  G81315DD
GlyGen:  G81315DD
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MV8 (Subject of Investigation/LOI)
Query on MV8

Download Ideal Coordinates CCD File 
NA [auth D],
Y [auth B]
(4-{[(5R)-3-(4-carbamimidoylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}piperazin-1-yl)acetic acid
C17 H23 N5 O4
BXTGCIBGRDGLNI-CQSZACIVSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
LA [auth D],
X [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
AA [auth C]
BA [auth C]
HA [auth C]
M [auth A]
N [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
MN
Query on MN

Download Ideal Coordinates CCD File 
IA [auth D]
JA [auth D]
KA [auth D]
U [auth B]
V [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
DA [auth C]
EA [auth C]
FA [auth C]
GA [auth C]
O [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL
Query on CL

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

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.231 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.221 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 258.55α = 90
b = 144.46β = 90
c = 105.1γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted MV8Click on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)United StatesHL-103526

Revision History  (Full details and data files)

  • Version 1.0: 2022-08-17
    Type: Initial release
  • Version 1.1: 2023-03-08
    Changes: Database references
  • Version 1.2: 2023-10-25
    Changes: Data collection, Refinement description
  • Version 1.3: 2024-10-02
    Changes: Structure summary
  • Version 1.4: 2024-11-20
    Changes: Structure summary