1M4B

Crystal Structure of Human Interleukin-2 K43C Covalently Modified at C43 with 2-[2-(2-Cyclohexyl-2-guanidino-acetylamino)-acetylamino]-N-(3-mercapto-propyl)-propionamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.245 
  • R-Value Observed: 0.247 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Binding of small molecules to an adaptive protein-protein interface

Arkin, M.A.Randal, M.DeLano, W.L.Hyde, J.Luong, T.N.Oslob, J.D.Raphael, D.R.Taylor, L.Wang, J.McDowell, R.S.Wells, J.A.Braisted, A.C.

(2003) Proc Natl Acad Sci U S A 100: 1603-1608

  • DOI: https://doi.org/10.1073/pnas.252756299
  • Primary Citation of Related Structures:  
    1M47, 1M48, 1M49, 1M4A, 1M4B, 1M4C

  • PubMed Abstract: 

    Understanding binding properties at protein-protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al. (1997) J. Am. Chem. Soc. 119, 7589-7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 alpha receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.


  • Organizational Affiliation

    Department of Biology, Sunesis Pharmaceuticals, South San Francisco, CA 94080-1913, USA. mra@sunesis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
interleukin-2133Homo sapiensMutation(s): 1 
UniProt & NIH Common Fund Data Resources
Find proteins for P60568 (Homo sapiens)
Explore P60568 
Go to UniProtKB:  P60568
PHAROS:  P60568
GTEx:  ENSG00000109471 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP60568
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NMP
Query on NMP

Download Ideal Coordinates CCD File 
B [auth A]2-[2-(2-CYCLOHEXYL-2-GUANIDINO-ACETYLAMINO)-ACETYLAMINO]-N-(3-MERCAPTO-PROPYL)-PROPIONAMIDE
C17 H32 N6 O3 S
YLLNYDDZOMCFDE-SMDDNHRTSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.286 
  • R-Value Work: 0.245 
  • R-Value Observed: 0.247 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.488α = 90
b = 35.102β = 97.52
c = 36.642γ = 90
Software Package:
Software NamePurpose
d*TREKdata reduction
AMoREphasing
REFMACrefinement
d*TREKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2002-07-31
    Type: Initial release
  • Version 1.1: 2008-04-28
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2021-10-27
    Changes: Database references, Derived calculations