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PDBsum entry 1q8w
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Transferase/transferase inhibitor PDB id
1q8w

 

 

 

 

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Contents
Protein chains
337 a.a. *
20 a.a. *
Ligands
M77
Waters ×86
* Residue conservation analysis
PDB id:
1q8w
Name: Transferase/transferase inhibitor
Title: The catalytic subunit of camp-dependent protein kinase in complex with rho-kinase inhibitor fasudil (ha-1077)
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: a. Fragment: catalytic subunit. Synonym: pka c-alpha, protein kinase a. Engineered: yes. Camp-dependent protein kinase inhibitor, alpha form. Chain: b. Fragment: residues 5-24. Synonym: pki-alpha, camp-dependent protein kinase inhibitor,
Source: Bos taurus. Cattle. Organism_taxid: 9913. Gene: prkaca. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: the protein was chemically synthesized.
Biol. unit: Dimer (from PQS)
Resolution:
2.20Å     R-factor:   0.220     R-free:   0.295
Authors: C.Breitenlechner,M.Gassel,H.Hidaka,V.Kinzel,R.Huber,R.A.Engh, D.Bossemeyer
Key ref:
C.Breitenlechner et al. (2003). Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity. Structure, 11, 1595-1607. PubMed id: 14656443 DOI: 10.1016/j.str.2003.11.002
Date:
22-Aug-03     Release date:   16-Dec-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha from Bos taurus
Seq:
Struc: 		351 a.a.
337 a.a.*
Protein chain
Pfam   ArchSchema ?
P61926  (IPKA_RABIT) -  cAMP-dependent protein kinase inhibitor alpha from Oryctolagus cuniculus
Seq:
Struc: 		76 a.a.
20 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain A: E.C.2.7.11.11  - cAMP-dependent 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: 10.1016/j.str.2003.11.002 Structure 11:1595-1607 (2003)
PubMed id: 14656443  
 
 
Protein kinase A in complex with Rho-kinase inhibitors Y-27632, Fasudil, and H-1152P: structural basis of selectivity.
C.Breitenlechner, M.Gassel, H.Hidaka, V.Kinzel, R.Huber, R.A.Engh, D.Bossemeyer.
 
  ABSTRACT  
 
Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators.
 
  Selected figure(s)  
 
Figure 6.
Figure 6. Comparison of HA-1077 and H-1152POverlay of HA-1077 and H-1152P demonstrates the colocalization of the isoquinoline atoms with respect to the surrounding residues. Both inhibitor molecules form an H bond to the backbone amide of Val123 in the hinge region. The position of the homopiperazine rings, however, diverge by ca. 1.5 Å. Consequently, H bonds between the homopiperazine nitrogen and Glu127 and Glu170 are formed only in the PKA-1077 complex. The contact between C10 and Thr183, which prevents as a steric clash a HA-1077-like positioning of the H-1152P homopiperazine ring, is shown as a red double arrow.
 
  The above figure is reprinted by permission from Cell Press: Structure (2003, 11, 1595-1607) copyright 2003.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20882561 A.Mihaescu, S.Santén, B.Jeppsson, and H.Thorlacius (2011).
Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction.
  Br J Surg, 98, 124-131.  
21087804 H.Shimada, N.R.Staten, and L.E.Rajagopalan (2011).
TGF-β1 mediated activation of Rho kinase induces TGF-β2 and endothelin-1 expression in human hepatic stellate cells.
  J Hepatol, 54, 521-528.  
21327630 J.Shi, L.Zhang, and L.Wei (2011).
Rho-kinase in development and heart failure: insights from genetic models.
  Pediatr Cardiol, 32, 297-304.  
21063203 T.Hata, J.Soga, T.Hidaka, N.Idei, Y.Fujii, N.Fujimura, S.Mikami, T.Maruhashi, Y.Kihara, K.Chayama, H.Kato, K.Noma, J.K.Liao, and Y.Higashi (2011).
Calcium channel blocker and Rho-associated kinase activity in patients with hypertension.
  J Hypertens, 29, 373-379.  
19936759 B.Zoer, C.E.Blanco, and E.Villamor (2010).
Role of Rho-kinase in mediating contraction of chicken embryo femoral arteries.
  J Comp Physiol B, 180, 427-435.  
20368772 D.W.Nuno, and K.G.Lamping (2010).
The role of rho kinase in sex-dependent vascular dysfunction in type 1 diabetes.
  Exp Diabetes Res, 2010, 176361.  
18704950 K.O.Wrzeszczynski, and B.Rost (2009).
Cell cycle kinases predicted from conserved biophysical properties.
  Proteins, 74, 655-668.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
19243496 S.J.Kim, J.H.Kim, J.M.Sun, M.G.Kim, and J.W.Oh (2009).
Suppression of hepatitis C virus replication by protein kinase C-related kinase 2 inhibitors that block phosphorylation of viral RNA polymerase.
  J Viral Hepat, 16, 697-704.  
18817543 E.O.Fuentes, J.Leemhuis, G.B.Stark, and E.M.Lang (2008).
Rho kinase inhibitors Y27632 and H1152 augment neurite extension in the presence of cultured Schwann cells.
  J Brachial Plex Peripher Nerve Inj, 3, 19.  
18973168 H.Schirok, R.Kast, S.Figueroa-Pérez, S.Bennabi, M.J.Gnoth, A.Feurer, H.Heckroth, M.Thutewohl, H.Paulsen, A.Knorr, J.Hütter, M.Lobell, K.Münter, V.Geiss, H.Ehmke, D.Lang, M.Radtke, J.Mittendorf, and J.P.Stasch (2008).
Design and synthesis of potent and selective azaindole-based Rho kinase (ROCK) inhibitors.
  ChemMedChem, 3, 1893-1904.  
18178218 J.Shi, Y.W.Zhang, L.J.Summers, G.W.Dorn, and L.Wei (2008).
Disruption of ROCK1 gene attenuates cardiac dilation and improves contractile function in pathological cardiac hypertrophy.
  J Mol Cell Cardiol, 44, 551-560.  
18415022 K.Gohda, and T.Hakoshima (2008).
A molecular mechanism of P-loop pliability of Rho-kinase investigated by molecular dynamic simulation.
  J Comput Aided Mol Des, 22, 789-797.  
17347801 J.Shi, and L.Wei (2007).
Rho kinase in the regulation of cell death and survival.
  Arch Immunol Ther Exp (Warsz), 55, 61-75.  
17934515 R.Kast, H.Schirok, S.Figueroa-Pérez, J.Mittendorf, M.J.Gnoth, H.Apeler, J.Lenz, J.K.Franz, A.Knorr, J.Hütter, M.Lobell, K.Zimmermann, K.Münter, K.H.Augstein, H.Ehmke, and J.P.Stasch (2007).
Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase.
  Br J Pharmacol, 152, 1070-1080.  
17036304 C.S.Page, and P.A.Bates (2006).
Can MM-PBSA calculations predict the specificities of protein kinase inhibitors?
  J Comput Chem, 27, 1990-2007.  
16531242 H.Yamaguchi, M.Kasa, M.Amano, K.Kaibuchi, and T.Hakoshima (2006).
Molecular mechanism for the regulation of rho-kinase by dimerization and its inhibition by fasudil.
  Structure, 14, 589-600.
PDB code: 2f2u
16249095 I.Collins, J.Caldwell, T.Fonseca, A.Donald, V.Bavetsias, L.J.Hunter, M.D.Garrett, M.G.Rowlands, G.W.Aherne, T.G.Davies, V.Berdini, S.J.Woodhead, D.Davis, L.C.Seavers, P.G.Wyatt, P.Workman, and E.McDonald (2006).
Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B.
  Bioorg Med Chem, 14, 1255-1273.
PDB codes: 2c1a 2c1b
16249185 M.Jacobs, K.Hayakawa, L.Swenson, S.Bellon, M.Fleming, P.Taslimi, and J.Doran (2006).
The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.
  J Biol Chem, 281, 260-268.
PDB codes: 2erz 2esm 2etk 2eto 2etr 3d9v
16699172 S.Bonn, S.Herrero, C.B.Breitenlechner, A.Erlbruch, W.Lehmann, R.A.Engh, M.Gassel, and D.Bossemeyer (2006).
Structural analysis of protein kinase A mutants with Rho-kinase inhibitor specificity.
  J Biol Chem, 281, 24818-24830.
PDB codes: 2gfc 2gnf 2gng 2gnh 2gni 2gnj 2gnl
15864268 B.K.Mueller, H.Mack, and N.Teusch (2005).
Rho kinase, a promising drug target for neurological disorders.
  Nat Rev Drug Discov, 4, 387-398.  
16185153 B.M.Klebl, and G.Müller (2005).
Second-generation kinase inhibitors.
  Expert Opin Ther Targets, 9, 975-993.  
15710979 C.Bourgier, V.Haydont, F.Milliat, A.François, V.Holler, P.Lasser, J.Bourhis, D.Mathé, and M.C.Vozenin-Brotons (2005).
Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression.
  Gut, 54, 336-343.  
16083339 E.Hu, and D.Lee (2005).
Rho kinase as potential therapeutic target for cardiovascular diseases: opportunities and challenges.
  Expert Opin Ther Targets, 9, 715-736.  
16305311 G.Kéri, Z.Székelyhidi, P.Bánhegyi, Z.Varga, B.Hegymegi-Barakonyi, C.Szántai-Kis, D.Hafenbradl, B.Klebl, G.Muller, A.Ullrich, D.Erös, Z.Horváth, Z.Greff, J.Marosfalvi, J.Pató, I.Szabadkai, I.Szilágyi, Z.Szegedi, I.Varga, F.Wáczek, and L.Orfi (2005).
Drug discovery in the kinase inhibitory field using the Nested Chemical Library technology.
  Assay Drug Dev Technol, 3, 543-551.  
15731862 J.López-Prados, F.Cuevas, N.C.Reichardt, J.L.de Paz, E.Q.Morales, and M.Martín-Lomas (2005).
Design and synthesis of inositolphosphoglycan putative insulin mediators.
  Org Biomol Chem, 3, 764-786.  
15549676 R.L.Rich, and D.G.Myszka (2005).
Survey of the year 2003 commercial optical biosensor literature.
  J Mol Recognit, 18, 1.  
15292186 L.Jin, S.Pluskey, E.C.Petrella, S.M.Cantin, J.C.Gorga, M.J.Rynkiewicz, P.Pandey, J.E.Strickler, R.E.Babine, D.T.Weaver, and K.J.Seidl (2004).
The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.
  J Biol Chem, 279, 42818-42825.
PDB code: 1u59
14996846 M.Gassel, C.B.Breitenlechner, N.König, R.Huber, R.A.Engh, and D.Bossemeyer (2004).
The protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase A.
  J Biol Chem, 279, 23679-23690.
PDB code: 1szm
15481030 T.Langer, M.Vogtherr, B.Elshorst, M.Betz, U.Schieborr, K.Saxena, and H.Schwalbe (2004).
NMR backbone assignment of a protein kinase catalytic domain by a combination of several approaches: application to the catalytic subunit of cAMP-dependent protein kinase.
  Chembiochem, 5, 1508-1516.  
15364937 Z.B.Xu, D.Chaudhary, S.Olland, S.Wolfrom, R.Czerwinski, K.Malakian, L.Lin, M.L.Stahl, D.Joseph-McCarthy, C.Benander, L.Fitz, R.Greco, W.S.Somers, and L.Mosyak (2004).
Catalytic domain crystal structure of protein kinase C-theta (PKCtheta).
  J Biol Chem, 279, 50401-50409.
PDB code: 1xjd
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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