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PDBsum entry 2g1q
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protein ligands metals Protein-protein interface(s) links
Cell cycle PDB id
2g1q

 

 

 

 

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JSmol PyMol  
Contents
Protein chains
330 a.a. *
Ligands
ADP ×2
N9H ×2
Metals
_MG ×2
Waters ×169
* Residue conservation analysis
PDB id:
2g1q
Name: Cell cycle
Title: Crystal structure of ksp in complex with inhibitor 9h
Structure: Kinesin-like protein kif11. Chain: a, b. Synonym: kinesin-related motor protein eg5, kinesin-like spindle protein hksp, thyroid receptor-interacting protein 5, trip5, kinesin- like protein 1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: kif11, eg5, knsl1. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Resolution:
2.51Å     R-factor:   0.234     R-free:   0.279
Authors: Y.Yan
Key ref: C.D.Cox et al. (2006). Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP. Bioorg Med Chem Lett, 16, 3175-3179. PubMed id: 16603356 DOI: 10.1016/j.bmcl.2006.03.040
Date:
14-Feb-06     Release date:   03-Oct-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P52732  (KIF11_HUMAN) -  Kinesin-like protein KIF11 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1056 a.a.
330 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1016/j.bmcl.2006.03.040 Bioorg Med Chem Lett 16:3175-3179 (2006)
PubMed id: 16603356  
 
 
Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP.
C.D.Cox, M.Torrent, M.J.Breslin, B.J.Mariano, D.B.Whitman, P.J.Coleman, C.A.Buser, E.S.Walsh, K.Hamilton, M.D.Schaber, R.B.Lobell, W.Tao, V.J.South, N.E.Kohl, Y.Yan, L.C.Kuo, T.Prueksaritanont, D.E.Slaughter, C.Li, E.Mahan, B.Lu, G.D.Hartman.
 
  ABSTRACT  
 
Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19483335 C.Jiang, Q.You, F.Liu, W.Wu, Q.Guo, J.Chern, L.Yang, and M.Chen (2009).
Design, synthesis and evaluation of tetrahydroisoquinolines as new kinesin spindle protein inhibitors.
  Chem Pharm Bull (Tokyo), 57, 567-571.  
19156502 D.Huszar, M.E.Theoclitou, J.Skolnik, and R.Herbst (2009).
Kinesin motor proteins as targets for cancer therapy.
  Cancer Metastasis Rev, 28, 197-208.  
19707665 O.Mahé, D.Frath, I.Dez, F.Marsais, V.Levacher, and J.F.Brière (2009).
TBD-organocatalysed synthesis of pyrazolines.
  Org Biomol Chem, 7, 3648-3651.  
17588180 C.Jiang, Y.Chen, X.Wang, and Q.You (2007).
Docking studies on kinesin spindle protein inhibitors: an important cooperative 'minor binding pocket' which increases the binding affinity significantly.
  J Mol Model, 13, 987-992.  
17251189 I.Garcia-Saez, S.DeBonis, R.Lopez, F.Trucco, B.Rousseau, P.Thuéry, and F.Kozielski (2007).
Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the R configuration.
  J Biol Chem, 282, 9740-9747.
PDB code: 2ieh
17922005 L.Luo, C.A.Parrish, N.Nevins, D.E.McNulty, A.M.Chaudhari, J.D.Carson, V.Sudakin, A.N.Shaw, R.Lehr, H.Zhao, S.Sweitzer, L.Lad, K.W.Wood, R.Sakowicz, R.S.Annan, P.S.Huang, J.R.Jackson, D.Dhanak, R.A.Copeland, and K.R.Auger (2007).
ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism.
  Nat Chem Biol, 3, 722-726.  
17206829 S.Manyem, M.P.Sibi, G.H.Lushington, B.Neuenswander, F.Schoenen, and J.Aubé (2007).
Solution-phase parallel synthesis of a library of delta(2)-pyrazolines.
  J Comb Chem, 9, 20-28.  
17014086 J.C.Cochran, T.C.Krzysiak, and S.P.Gilbert (2006).
Pathway of ATP hydrolysis by monomeric kinesin Eg5.
  Biochemistry, 45, 12334-12344.  
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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