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PDBsum entry 2br1
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protein ligands links
Transferase PDB id
2br1

 

 

 

 

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Contents
Protein chain
272 a.a. *
Ligands
PFP
SO4 ×2
Waters ×302
* Residue conservation analysis
PDB id:
2br1
Name: Transferase
Title: Structure-based design of novel chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity
Structure: Serine/threonine-protein kinase chk1. Chain: a. Fragment: n-terminal kinase domain residues 1-289. Synonym: chk1 kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.00Å     R-factor:   0.163     R-free:   0.226
Authors: N.Foloppe,L.M.Fisher,R.Howes,P.Kierstan,A.Potter,A.G.S.Robertson, A.E.Surgenor
Key ref: N.Foloppe et al. (2005). Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. J Med Chem, 48, 4332-4345. PubMed id: 15974586 DOI: 10.1021/jm049022c
Date:
29-Apr-05     Release date:   12-May-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O14757  (CHK1_HUMAN) -  Serine/threonine-protein kinase Chk1 from Homo sapiens
Seq:
Struc: 		476 a.a.
272 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction:
1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
L-seryl-[protein]
 + ATP
 = O-phospho-L-seryl-[protein]
 + ADP
 + H(+)
L-threonyl-[protein]
 + ATP
 = O-phospho-L-threonyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    reference    
 
 
DOI no: 10.1021/jm049022c J Med Chem 48:4332-4345 (2005)
PubMed id: 15974586  
 
 
Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity.
N.Foloppe, L.M.Fisher, R.Howes, P.Kierstan, A.Potter, A.G.Robertson, A.E.Surgenor.
 
  ABSTRACT  
 
We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21374633 H.G.Wallnoefer, K.R.Liedl, and T.Fox (2011).
A challenging system: Free energy prediction for factor Xa.
  J Comput Chem, 32, 1743-1752.  
20976184 A.J.Massey, J.Borgognoni, C.Bentley, N.Foloppe, A.Fiumana, and L.Walmsley (2010).
Context-dependent cell cycle checkpoint abrogation by a novel kinase inhibitor.
  PLoS One, 5, e13123.
PDB code: 3nlb
20345171 C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.
  J Med Chem, 53, 5061-5084.  
20039358 M.S.Coumar, M.T.Tsai, C.Y.Chu, B.J.Uang, W.H.Lin, C.Y.Chang, T.Y.Chang, J.S.Leou, C.H.Teng, J.S.Wu, M.Y.Fang, C.H.Chen, J.T.Hsu, S.Y.Wu, Y.S.Chao, and H.P.Hsieh (2010).
Identification, SAR studies, and X-ray co-crystallographic analysis of a novel furanopyrimidine aurora kinase A inhibitor.
  ChemMedChem, 5, 255-267.
PDB code: 3k5u
19444816 B.R.Brooks, C.L.Brooks, A.D.Mackerell, L.Nilsson, R.J.Petrella, B.Roux, Y.Won, G.Archontis, C.Bartels, S.Boresch, A.Caflisch, L.Caves, Q.Cui, A.R.Dinner, M.Feig, S.Fischer, J.Gao, M.Hodoscek, W.Im, K.Kuczera, T.Lazaridis, J.Ma, V.Ovchinnikov, E.Paci, R.W.Pastor, C.B.Post, J.Z.Pu, M.Schaefer, B.Tidor, R.M.Venable, H.L.Woodcock, X.Wu, W.Yang, D.M.York, and M.Karplus (2009).
CHARMM: the biomolecular simulation program.
  J Comput Chem, 30, 1545-1614.  
19350606 T.Castaño, H.Wang, N.E.Campillo, S.Ballester, C.González-García, J.Hernández, C.Pérez, J.Cuenca, A.Pérez-Castillo, A.Martínez, O.Huertas, J.L.Gelpí, F.J.Luque, H.Ke, and C.Gil (2009).
Synthesis, structural analysis, and biological evaluation of thioxoquinazoline derivatives as phosphodiesterase 7 inhibitors.
  ChemMedChem, 4, 866-876.
PDB code: 3g3n
17936059 C.McInnes (2007).
Virtual screening strategies in drug discovery.
  Curr Opin Chem Biol, 11, 494-502.  
17854022 K.L.Arrington, and V.Y.Dudkin (2007).
Novel Inhibitors of Checkpoint Kinase 1.
  ChemMedChem, 2, 1571-1585.  
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.

 

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