PDBsum entry 3hrc

Go to PDB code: 
protein ligands links
Transferase PDB id
Jmol PyMol
Protein chain
280 a.a. *
Waters ×178
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Crystal structure of a mutant of human pdk1 kinase domain in with atp
Structure: 3-phosphoinositide-dependent protein kinase 1. Chain: a. Fragment: pdk1 kinase domain. Synonym: hpdk1. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pdk1, pdpk1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
1.91Å     R-factor:   0.182     R-free:   0.207
Authors: V.Hindie,P.M.Alzari,R.M.Biondi
Key ref: V.Hindie et al. (2009). Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol, 5, 758-764. PubMed id: 19718043
09-Jun-09     Release date:   15-Sep-09    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O15530  (PDPK1_HUMAN) -  3-phosphoinositide-dependent protein kinase 1
556 a.a.
280 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
Bound ligand (Het Group name = ATP)
corresponds exactly
+ protein
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     2 terms  


Nat Chem Biol 5:758-764 (2009)
PubMed id: 19718043  
Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1.
V.Hindie, A.Stroba, H.Zhang, L.A.Lopez-Garcia, L.Idrissova, S.Zeuzem, D.Hirschberg, F.Schaeffer, T.J.Jørgensen, M.Engel, P.M.Alzari, R.M.Biondi.
Protein phosphorylation transduces a large set of intracellular signals. One mechanism by which phosphorylation mediates signal transduction is by prompting conformational changes in the target protein or interacting proteins. Previous work described an allosteric site mediating phosphorylation-dependent activation of AGC kinases. The AGC kinase PDK1 is activated by the docking of a phosphorylated motif from substrates. Here we present the crystallography of PDK1 bound to a rationally developed low-molecular-weight activator and describe the conformational changes induced by small compounds in the crystal and in solution using a fluorescence-based assay and deuterium exchange experiments. Our results indicate that the binding of the compound produces local changes at the target site, the PIF binding pocket, and also allosteric changes at the ATP binding site and the activation loop. Altogether, we present molecular details of the allosteric changes induced by small compounds that trigger the activation of PDK1 through mimicry of phosphorylation-dependent conformational changes.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21428922 A.J.Cameron (2011).
Occupational hazards: allosteric regulation of protein kinases through the nucleotide-binding pocket.
  Biochem Soc Trans, 39, 472-476.  
21430264 J.D.Sadowsky, M.A.Burlingame, D.W.Wolan, C.L.McClendon, M.P.Jacobson, and J.A.Wells (2011).
Turning a protein kinase on or off from a single allosteric site via disulfide trapping.
  Proc Natl Acad Sci U S A, 108, 6056-6061.
PDB codes: 3orx 3orz 3otu
21474065 N.Jura, X.Zhang, N.F.Endres, M.A.Seeliger, T.Schindler, and J.Kuriyan (2011).
Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms.
  Mol Cell, 42, 9.  
20044479 A.T.Alberobello, V.D'Esposito, D.Marasco, N.Doti, M.Ruvo, R.Bianco, G.Tortora, I.Esposito, F.Fiory, C.Miele, F.Beguinot, and P.Formisano (2010).
Selective disruption of insulin-like growth factor-1 (IGF-1) signaling via phosphoinositide-dependent kinase-1 prevents the protective effect of IGF-1 on human cancer cell death.
  J Biol Chem, 285, 6563-6572.  
20839295 C.J.Illingworth, P.D.Scott, K.E.Parkes, C.R.Snell, M.P.Campbell, and C.A.Reynolds (2010).
Connectivity and binding-site recognition: applications relevant to drug design.
  J Comput Chem, 31, 2677-2688.  
20130576 G.Hatzivassiliou, K.Song, I.Yen, B.J.Brandhuber, D.J.Anderson, R.Alvarado, M.J.Ludlam, D.Stokoe, S.L.Gloor, G.Vigers, T.Morales, I.Aliagas, B.Liu, S.Sideris, K.P.Hoeflich, B.S.Jaiswal, S.Seshagiri, H.Koeppen, M.Belvin, L.S.Friedman, and S.Malek (2010).
RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.
  Nature, 464, 431-435.
PDB codes: 3lb7 3omv
20500829 G.Williams (2010).
Elastic network model of allosteric regulation in protein kinase PDK1.
  BMC Struct Biol, 10, 11.  
21105670 I.Buch, D.Fishelovitch, N.London, B.Raveh, H.J.Wolfson, and R.Nussinov (2010).
Allosteric regulation of glycogen synthase kinase 3β: a theoretical study.
  Biochemistry, 49, 10890-10901.  
20154666 J.A.Zorn, and J.A.Wells (2010).
Turning enzymes ON with small molecules.
  Nat Chem Biol, 6, 179-188.  
20027184 L.R.Pearce, D.Komander, and D.R.Alessi (2010).
The nuts and bolts of AGC protein kinases.
  Nat Rev Mol Cell Biol, 11, 9.  
20154661 O.Fedorov, S.Müller, and S.Knapp (2010).
The (un)targeted cancer kinome.
  Nat Chem Biol, 6, 166-169.  
19723632 R.Dettori, S.Sonzogni, L.Meyer, L.A.Lopez-Garcia, N.A.Morrice, S.Zeuzem, M.Engel, A.Piiper, S.Neimanis, M.Frödin, and R.M.Biondi (2009).
Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1).
  J Biol Chem, 284, 30318-30327.  
19779441 Y.Liu (2009).
Chemical biology: Caught in the activation.
  Nature, 461, 484-485.  
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 codes are shown on the right.