PDBsum entry 2gvd

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protein ligands metals Protein-protein interface(s) links
Lyase PDB id
Protein chains
190 a.a. *
189 a.a. *
322 a.a. *
_MN ×3
Waters ×51
* Residue conservation analysis
PDB id:
Name: Lyase
Title: Complex of gs- with the catalytic domains of mammalian adeny cyclase: complex with tnp-atp and mn
Structure: Adenylate cyclase type 5. Chain: a. Fragment: c1a domain, residues 440-657. Synonym: adenylate cyclase type v, atp pyrophosphate-lyase adenylyl cyclase 5, ca2+, -inhibitable adenylyl cyclase. Engineered: yes. Adenylate cyclase type 2. Chain: b. Fragment: c2a domain, residues 870-1081.
Source: Canis lupus familiaris. Dog. Organism_taxid: 9615. Strain: familiaris. Gene: adcy5. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Rattus norvegicus. Norway rat.
Biol. unit: Trimer (from PQS)
2.90Å     R-factor:   0.245     R-free:   0.279
Authors: T.-C.Mou,S.R.Sprang
Key ref: T.C.Mou et al. (2006). Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors. Mol Pharmacol, 70, 878-886. PubMed id: 16766715 DOI: 10.1124/mol.106.026427
02-May-06     Release date:   04-Jul-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P30803  (ADCY5_CANFA) -  Adenylate cyclase type 5
1265 a.a.
190 a.a.*
Protein chain
Pfam   ArchSchema ?
P26769  (ADCY2_RAT) -  Adenylate cyclase type 2
1090 a.a.
189 a.a.
Protein chain
Pfam   ArchSchema ?
P04896  (GNAS2_BOVIN) -  Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
394 a.a.
322 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Adenylate cyclase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP = 3',5'-cyclic AMP + diphosphate
Bound ligand (Het Group name = 128)
matches with 67.39% similarity
= 3',5'-cyclic AMP
+ diphosphate
      Cofactor: Pyridoxal 5'-phosphate
Pyridoxal 5'-phosphate
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  


DOI no: 10.1124/mol.106.026427 Mol Pharmacol 70:878-886 (2006)
PubMed id: 16766715  
Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors.
T.C.Mou, A.Gille, S.Suryanarayana, M.Richter, R.Seifert, S.R.Sprang.
Membrane adenylyl cyclases (mACs) play an important role in signal transduction and are therefore potential drug targets. Earlier, we identified 2',3'-O-(N-methylanthraniloyl) (MANT)-substituted purine nucleotides as a novel class of highly potent competitive mAC inhibitors (Ki values in the 10 nM range). MANT nucleotides discriminate among various mAC isoforms through differential interactions with a binding pocket localized at the interface between the C1 and C2 domains of mAC. In this study, we examine the structure/activity relationships for 2',3'-substituted nucleotides and compare the crystal structures of mAC catalytic domains (VC1:IIC2) bound to MANT-GTP, MANT-ATP, and 2',3'-(2,4,6-trinitrophenyl) (TNP)-ATP. TNP-substituted purine and pyrimidine nucleotides inhibited VC1:IIC2 with moderately high potency (Ki values in the 100 nM range). Elongation of the linker between the ribosyl group and the MANT group and substitution of N-adenine atoms with MANT reduces inhibitory potency. Crystal structures show that MANT-GTP, MANT-ATP, and TNP-ATP reside in the same binding pocket in the VC1:IIC2 protein complex, but there are substantial differences in interactions of base, fluorophore, and polyphosphate chain of the inhibitors with mAC. Fluorescence emission and resonance transfer spectra also reflect differences in the interaction between MANT-ATP and VC1:IIC2 relative to MANT-GTP. Our data are indicative of a three-site mAC pharmacophore; the 2',3'-O-ribosyl substituent and the polyphosphate chain have the largest impact on inhibitor affinity and the nucleotide base has the least. The mAC binding site exhibits broad specificity, accommodating various bases and fluorescent groups at the 2',3'-O-ribosyl position. These data should greatly facilitate the rational design of potent, isoform-selective mAC inhibitors.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21239683 C.Toyoshima, S.Yonekura, J.Tsueda, and S.Iwasawa (2011).
Trinitrophenyl derivatives bind differently from parent adenine nucleotides to Ca2+-ATPase in the absence of Ca2+.
  Proc Natl Acad Sci U S A, 108, 1833-1838.
PDB codes: 3ar2 3ar3 3ar4 3ar5 3ar6 3ar7 3ar8 3ar9
21484439 M.Hübner, S.Dizayee, J.Matthes, R.Seifert, and S.Herzig (2011).
Effect of MANT-nucleotides on L-type calcium currents in murine cardiomyocytes.
  Naunyn Schmiedebergs Arch Pharmacol, 383, 573-583.  
19638320 B.Pavan, C.Biondi, and A.Dalpiaz (2009).
Adenylyl cyclases as innovative therapeutic goals.
  Drug Discov Today, 14, 982-991.  
19447224 C.Pinto, M.Hübner, A.Gille, M.Richter, T.C.Mou, S.R.Sprang, and R.Seifert (2009).
Differential interactions of the catalytic subunits of adenylyl cyclase with forskolin analogs.
  Biochem Pharmacol, 78, 62-69.  
19056899 H.M.Taha, J.Schmidt, M.Göttle, S.Suryanarayana, Y.Shen, W.J.Tang, A.Gille, J.Geduhn, B.König, S.Dove, and R.Seifert (2009).
Molecular analysis of the interaction of anthrax adenylyl cyclase toxin, edema factor, with 2'(3')-O-(N-(methyl)anthraniloyl)-substituted purine and pyrimidine nucleotides.
  Mol Pharmacol, 75, 693-703.  
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.  
19492438 S.Suryanarayana, J.L.Wang, M.Richter, Y.Shen, W.J.Tang, G.H.Lushington, and R.Seifert (2009).
Distinct interactions of 2'- and 3'-O-(N-methyl)anthraniloyl-isomers of ATP and GTP with the adenylyl cyclase toxin of Bacillus anthracis, edema factor.
  Biochem Pharmacol, 78, 224-230.  
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
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.  
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.