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PDBsum entry 1cs4

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protein ligands metals Protein-protein interface(s) links
Lyase/lyase/signaling protein PDB id
1cs4
Jmol
Contents
Protein chains
189 a.a. *
190 a.a. *
329 a.a. *
Ligands
FOK
MES ×2
POP
101
GSP
Metals
_MG ×2
_CL
Waters ×77
* Residue conservation analysis
PDB id:
1cs4
Name: Lyase/lyase/signaling protein
Title: Complex of gs-alpha with the catalytic domains of mammalian adenylyl cyclase: complex with 2'-deoxy-adenosine 3'- monophosphate, pyrophosphate and mg
Structure: Type v adenylate cyclase. Chain: a. Fragment: c1a domain. Synonym: atp pyrophosphate-lyase. Engineered: yes. Mutation: yes. Type ii adenylate cyclase. Chain: b. Fragment: c2a domain.
Source: Canis lupus familiaris. Dog. Organism_taxid: 9615. Strain: familiaris. Organ: heart. Expressed in: escherichia coli. Expression_system_taxid: 562. Rattus norvegicus. Norway rat.
Biol. unit: Trimer (from PQS)
Resolution:
2.50Å     R-factor:   0.216     R-free:   0.264
Authors: J.J.G.Tesmer,C.A.Dessauer,R.K.Sunahara,R.A.Johnson, A.G.Gilman,S.R.Sprang
Key ref:
J.J.Tesmer et al. (2000). Molecular basis for P-site inhibition of adenylyl cyclase. Biochemistry, 39, 14464-14471. PubMed id: 11087399 DOI: 10.1021/bi0015562
Date:
16-Aug-99     Release date:   10-Jan-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P30803  (ADCY5_CANFA) -  Adenylate cyclase type 5
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1265 a.a.
189 a.a.*
Protein chain
Pfam   ArchSchema ?
P26769  (ADCY2_RAT) -  Adenylate cyclase type 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1090 a.a.
190 a.a.
Protein chain
Pfam   ArchSchema ?
P04896  (GNAS2_BOVIN) -  Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Seq:
Struc:
394 a.a.
329 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.4.6.1.1  - Adenylate cyclase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP = 3',5'-cyclic AMP + diphosphate
ATP
Bound ligand (Het Group name = GSP)
matches with 90.00% similarity
= 3',5'-cyclic AMP
+
diphosphate
Bound ligand (Het Group name = POP)
corresponds exactly
      Cofactor: Pyridoxal 5'-phosphate
Pyridoxal 5'-phosphate
Bound ligand (Het Group name = 101) matches with 46.00% similarity
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   4 terms 
  Biological process     intracellular signal transduction   32 terms 
  Biochemical function     nucleotide binding     8 terms  

 

 
    reference    
 
 
DOI no: 10.1021/bi0015562 Biochemistry 39:14464-14471 (2000)
PubMed id: 11087399  
 
 
Molecular basis for P-site inhibition of adenylyl cyclase.
J.J.Tesmer, C.W.Dessauer, R.K.Sunahara, L.D.Murray, R.A.Johnson, A.G.Gilman, S.R.Sprang.
 
  ABSTRACT  
 
P-site inhibitors are adenosine and adenine nucleotide analogues that inhibit adenylyl cyclase, the effector enzyme that catalyzes the synthesis of cyclic AMP from ATP. Some of these inhibitors may represent physiological regulators of adenylyl cyclase, and the most potent may ultimately serve as useful therapeutic agents. Described here are crystal structures of the catalytic core of adenylyl cyclase complexed with two such P-site inhibitors, 2'-deoxyadenosine 3'-monophosphate (2'-d-3'-AMP) and 2',5'-dideoxyadenosine 3'-triphosphate (2',5'-dd-3'-ATP). Both inhibitors bind in the active site yet exhibit non- or uncompetitive patterns of inhibition. While most P-site inhibitors require pyrophosphate (PP(i)) as a coinhibitor, 2',5'-dd-3'-ATP is a potent inhibitor by itself. The crystal structure reveals that this inhibitor exhibits two binding modes: one with the nucleoside moiety bound to the nucleoside binding pocket of the enzyme and the other with the beta and gamma phosphates bound to the pyrophosphate site of the 2'-d-3'-AMP.PP(i) complex. A single metal binding site is observed in the complex with 2'-d-3'-AMP, whereas two are observed in the complex with 2', 5'-dd-3'-ATP. Even though P-site inhibitors are typically 10 times more potent in the presence of Mn(2+), the electron density maps reveal no inherent preference of either metal site for Mn(2+) over Mg(2+). 2',5'-dd-3'-ATP binds to the catalytic core of adenylyl cyclase with a K(d) of 2.4 microM in the presence of Mg(2+) and 0.2 microM in the presence of Mn(2+). Pyrophosphate does not compete with 2',5'-dd-3'-ATP and enhances inhibition.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19638320 B.Pavan, C.Biondi, and A.Dalpiaz (2009).
Adenylyl cyclases as innovative therapeutic goals.
  Drug Discov Today, 14, 982-991.  
18948702 R.Sadana, and C.W.Dessauer (2009).
Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies.
  Neurosignals, 17, 5.  
19337273 S.Pierre, T.Eschenhagen, G.Geisslinger, and K.Scholich (2009).
Capturing adenylyl cyclases as potential drug targets.
  Nat Rev Drug Discov, 8, 321-335.  
19494187 S.Suryanarayana, M.Göttle, M.Hübner, A.Gille, T.C.Mou, S.R.Sprang, M.Richter, and R.Seifert (2009).
Differential inhibition of various adenylyl cyclase isoforms and soluble guanylyl cyclase by 2',3'-O-(2,4,6-trinitrophenyl)-substituted nucleoside 5'-triphosphates.
  J Pharmacol Exp Ther, 330, 687-695.  
19243146 T.C.Mou, N.Masada, D.M.Cooper, and S.R.Sprang (2009).
Structural basis for inhibition of mammalian adenylyl cyclase by calcium.
  Biochemistry, 48, 3387-3397.
PDB codes: 3c14 3c15 3c16 3e8a 3maa
18630896 C.Schlicker, A.Rauch, K.C.Hess, B.Kachholz, L.R.Levin, J.Buck, and C.Steegborn (2008).
Structure-based development of novel adenylyl cyclase inhibitors.
  J Med Chem, 51, 4456-4464.  
18461395 M.Nakachi, M.Matsumoto, P.M.Terry, R.L.Cerny, and H.Moriyama (2008).
Identification of guanylate cyclases and related signaling proteins in sperm tail from sea stars by mass spectrometry.
  Mar Biotechnol (NY), 10, 564-571.  
17329110 J.L.Wang, J.X.Guo, Q.Y.Zhang, J.J.Wu, R.Seifert, and G.H.Lushington (2007).
A conformational transition in the adenylyl cyclase catalytic site yields different binding modes for ribosyl-modified and unmodified nucleotide inhibitors.
  Bioorg Med Chem, 15, 2993-3002.  
16275644 S.Diel, K.Klass, B.Wittig, and C.Kleuss (2006).
Gbetagamma activation site in adenylyl cyclase type II. Adenylyl cyclase type III is inhibited by Gbetagamma.
  J Biol Chem, 281, 288-294.  
15890882 I.Tews, F.Findeisen, I.Sinning, A.Schultz, J.E.Schultz, and J.U.Linder (2005).
The structure of a pH-sensing mycobacterial adenylyl cyclase holoenzyme.
  Science, 308, 1020-1023.
PDB codes: 1y10 1y11
15678099 S.C.Sinha, M.Wetterer, S.R.Sprang, J.E.Schultz, and J.U.Linder (2005).
Origin of asymmetry in adenylyl cyclases: structures of Mycobacterium tuberculosis Rv1900c.
  EMBO J, 24, 663-673.
PDB codes: 1ybt 1ybu
15591060 T.C.Mou, A.Gille, D.A.Fancy, R.Seifert, and S.R.Sprang (2005).
Structural basis for the inhibition of mammalian membrane adenylyl cyclase by 2 '(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate.
  J Biol Chem, 280, 7253-7261.
PDB codes: 1tl7 1u0h
14981084 A.Gille, G.H.Lushington, T.C.Mou, M.B.Doughty, R.A.Johnson, and R.Seifert (2004).
Differential inhibition of adenylyl cyclase isoforms and soluble guanylyl cyclase by purine and pyrimidine nucleotides.
  J Biol Chem, 279, 19955-19969.  
15262973 K.Iwatsubo, S.Minamisawa, T.Tsunematsu, M.Nakagome, Y.Toya, J.E.Tomlinson, S.Umemura, R.M.Scarborough, D.E.Levy, and Y.Ishikawa (2004).
Direct inhibition of type 5 adenylyl cyclase prevents myocardial apoptosis without functional deterioration.
  J Biol Chem, 279, 40938-40945.  
15271985 M.Spehr, K.Schwane, J.A.Riffell, J.Barbour, R.K.Zimmer, E.M.Neuhaus, and H.Hatt (2004).
Particulate adenylate cyclase plays a key role in human sperm olfactory receptor-mediated chemotaxis.
  J Biol Chem, 279, 40194-40203.  
15131111 Q.Guo, Y.Shen, N.L.Zhukovskaya, J.Florián, and W.J.Tang (2004).
Structural and kinetic analyses of the interaction of anthrax adenylyl cyclase toxin with reaction products cAMP and pyrophosphate.
  J Biol Chem, 279, 29427-29435.
PDB code: 1sk6
15257286 S.C.Pierre, J.Häusler, K.Birod, G.Geisslinger, and K.Scholich (2004).
PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate.
  EMBO J, 23, 3031-3040.  
12783579 K.Iwatsubo, T.Tsunematsu, and Y.Ishikawa (2003).
Isoform-specific regulation of adenylyl cyclase: a potential target in future pharmacotherapy.
  Expert Opin Ther Targets, 7, 441-451.  
12676933 S.Soelaiman, B.Q.Wei, P.Bergson, Y.S.Lee, Y.Shen, M.Mrksich, B.K.Shoichet, and W.J.Tang (2003).
Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough.
  J Biol Chem, 278, 25990-25997.  
12058044 C.W.Dessauer, M.Chen-Goodspeed, and J.Chen (2002).
Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.
  J Biol Chem, 277, 28823-28829.  
12121994 M.A.D'Angelo, A.E.Montagna, S.Sanguineti, H.N.Torres, and M.M.Flawiá (2002).
A novel calcium-stimulated adenylyl cyclase from Trypanosoma cruzi, which interacts with the structural flagellar protein paraflagellar rod.
  J Biol Chem, 277, 35025-35034.  
  11602596 T.Onda, Y.Hashimoto, M.Nagai, H.Kuramochi, S.Saito, H.Yamazaki, Y.Toya, I.Sakai, C.J.Homcy, K.Nishikawa, and Y.Ishikawa (2001).
Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms.
  J Biol Chem, 276, 47785-47793.  
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.