5HI4

Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists.

Liu, S.Dakin, L.A.Xing, L.Withka, J.M.Sahasrabudhe, P.V.Li, W.Banker, M.E.Balbo, P.Shanker, S.Chrunyk, B.A.Guo, Z.Chen, J.M.Young, J.A.Bai, G.Starr, J.T.Wright, S.W.Bussenius, J.Tan, S.Gopalsamy, A.Lefker, B.A.Vincent, F.Jones, L.H.Xu, H.Hoth, L.R.Geoghegan, K.F.Qiu, X.Bunnage, M.E.Thorarensen, A.

(2016) Sci Rep 6: 30859-30859

  • DOI: https://doi.org/10.1038/srep30859
  • Primary Citation of Related Structures:  
    5HI3, 5HI4, 5HI5

  • PubMed Abstract: 

    Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.


  • Organizational Affiliation

    Worldwide Medicinal Chemistry, Pfizer Worldwide R&D, Eastern Point Road, Groton, CT 06340, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Interleukin-17A
A, B
132Homo sapiensMutation(s): 0 
Gene Names: IL17ACTLA8IL17
UniProt & NIH Common Fund Data Resources
Find proteins for Q16552 (Homo sapiens)
Explore Q16552 
Go to UniProtKB:  Q16552
PHAROS:  Q16552
GTEx:  ENSG00000112115 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ16552
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CAT-2000 FAB heavy chainC,
E [auth H]
237Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
CAT-2000 FAB light chainD,
G [auth L]
214Homo sapiensMutation(s): 0 
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  • Reference Sequence

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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
synthetic IL-17A peptide inhibitorF [auth I]16synthetic constructMutation(s): 0 
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
63P
Query on 63P

Download Ideal Coordinates CCD File 
H [auth A](9'S,17'R)-6'-chloro-N-methyl-9'-{[(1-methyl-1H-pyrazol-5-yl)carbonyl]amino}-10',19'-dioxo-2'-oxa-11',18'-diazaspiro[cyclopentane-1,21'-tetracyclo[20.2.2.2~12,15~.1~3,7~]nonacosane]-1'(24'),3'(29'),4',6',12',14',22',25',27'-nonaene-17'-carboxamide
C37 H39 Cl N6 O5
YLXUJTMICDNYSR-JSOSNVBQSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
63P Binding MOAD:  5HI4 IC50: 34 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.24α = 90
b = 68.19β = 91.33
c = 100.12γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
autoPROCdata scaling
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-08-31 
  • Deposition Author(s): Liu, S.

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-31
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Refinement description