spacer
spacer

PDBsum entry 1py2
Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Immune system PDB id
1py2

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chains
117 a.a. *
116 a.a. *
115 a.a. *
120 a.a. *
Ligands
FRH ×4
Metals
_ZN ×3
* Residue conservation analysis
PDB id:
1py2
Name: Immune system
Title: Structure of a 60 nm small molecule bound to a hot spot on il-2
Structure: Interleukin-2. Chain: a, b, c, d. Synonym: il-2, t-cell growth factor, tcgf, aldesleukin. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: il2. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.80Å     R-factor:   0.273     R-free:   0.320
Authors: C.D.Thanos,M.Randal,J.A.Wells
Key ref: C.D.Thanos et al. (2003). Potent small-molecule binding to a dynamic hot spot on IL-2. J Am Chem Soc, 125, 15280-15281. PubMed id: 14664558 DOI: 10.1021/ja0382617
Date:
07-Jul-03     Release date:   13-Jan-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
P60568  (IL2_HUMAN) -  Interleukin-2 from Homo sapiens
Seq:
Struc: 		153 a.a.
117 a.a.*
Protein chain
P60568  (IL2_HUMAN) -  Interleukin-2 from Homo sapiens
Seq:
Struc: 		153 a.a.
116 a.a.
Protein chain
P60568  (IL2_HUMAN) -  Interleukin-2 from Homo sapiens
Seq:
Struc: 		153 a.a.
115 a.a.
Protein chain
P60568  (IL2_HUMAN) -  Interleukin-2 from Homo sapiens
Seq:
Struc: 		153 a.a.
120 a.a.
Key:    Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
DOI no: 10.1021/ja0382617 J Am Chem Soc 125:15280-15281 (2003)
PubMed id: 14664558  
 
 
Potent small-molecule binding to a dynamic hot spot on IL-2.
C.D.Thanos, M.Randal, J.A.Wells.
 
  ABSTRACT  
 
The complexes between IL-2 and two similar small molecules, one a lead compound and the other a potent, affinity-optimized compound, were determined by X-ray crystallography. The lead compound (IC50 = 6 muM) bound to a hot spot on IL-2 in a groove that is not apparent in either the unliganded protein or a complex between IL-2 and a weakly bound drug fragment. The affinity-optimized compound (IC50 = 0.06 muM), which has an added aromatic acid fragment, bound in the same groove as the lead compound. In addition, a novel binding site was formed for the aromatic acid which is unseen in the complex with the lead compound. Thus, the hot spot on IL-2 is highly dynamic, with the protein changing form at multiple sites to maximize packing for each compound. Binding-site rigidity is often thought to play a role in high-affinity interactions. However, in this case, specific contacts between the small molecule and the protein are made despite the adaptivity of the hot spot. Given the change in morphology that was observed in IL-2, it is unlikely that a potent inhibitor could have been found by rational design. Therefore, fragment assembly methods offer the stochastic advantage of finding fragments in flexible protein regions where structural changes are unpredictable.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20544968 D.J.Diller, C.Humblet, X.Zhang, and L.M.Westerhoff (2010).
Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.
  Proteins, 78, 2329-2337.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
18382693 H.Zhu, I.Sommer, T.Lengauer, and F.S.Domingues (2008).
Alignment of non-covalent interactions at protein-protein interfaces.
  PLoS ONE, 3, e1926.  
18680750 P.J.Lupardus, and K.C.Garcia (2008).
The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12.
  J Mol Biol, 382, 931-941.
PDB code: 3duh
18412174 P.M.Fischer (2008).
Computational chemistry approaches to drug discovery in signal transduction.
  Biotechnol J, 3, 452-470.  
18075579 J.A.Wells, and C.L.McClendon (2007).
Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.
  Nature, 450, 1001-1009.  
17503422 J.D.Sadowsky, J.K.Murray, Y.Tomita, and S.H.Gellman (2007).
Exploration of backbone space in foldamers containing alpha- and beta-amino acid residues: developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL.
  Chembiochem, 8, 903-916.  
17032757 C.D.Thanos, W.L.DeLano, and J.A.Wells (2006).
Hot-spot mimicry of a cytokine receptor by a small molecule.
  Proc Natl Acad Sci U S A, 103, 15422-15427.
PDB code: 1qvn
16510978 D.E.Hurt, J.Widom, and J.Clardy (2006).
Structure of Plasmodium falciparum dihydroorotate dehydrogenase with a bound inhibitor.
  Acta Crystallogr D Biol Crystallogr, 62, 312-323.
PDB code: 1tv5
15550394 E.Buck, H.Bourne, and J.A.Wells (2005).
Site-specific disulfide capture of agonist and antagonist peptides on the C5a receptor.
  J Biol Chem, 280, 4009-4012.  
15139811 D.A.Erlanson, J.A.Wells, and A.C.Braisted (2004).
Tethering: fragment-based drug discovery.
  Annu Rev Biophys Biomol Struct, 33, 199-223.  
15288250 D.A.Erlanson, and S.K.Hansen (2004).
Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly.
  Curr Opin Chem Biol, 8, 399-406.  
15060526 M.R.Arkin, and J.A.Wells (2004).
Small-molecule inhibitors of protein-protein interactions: progressing towards the dream.
  Nat Rev Drug Discov, 3, 301-317.  
15300826 T.Berg (2004).
Use of "tethering" for the identification of a small molecule that binds to a dynamic hot spot on the interleukin-2 surface.
  Chembiochem, 5, 1051-1053.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

spacer
spacer