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protein metals links
Lyase PDB id
1fx4
Jmol
Contents
Protein chain
231 a.a. *
Metals
_MG
Waters ×264
* Residue conservation analysis
PDB id:
1fx4
Name: Lyase
Title: Structure analysis of adenylate cyclases from trypanosoma brucei in their monomeric state
Structure: Receptor-type adenylate cyclase gresag 4.3. Chain: a. Fragment: catalytic domain. Synonym: atp pyrophosphate-lyase, adenylyl cyclase. Engineered: yes
Source: Trypanosoma brucei. Organism_taxid: 5691. Strain: strain 927. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.90Å     R-factor:   0.202     R-free:   0.232
Authors: B.Bieger,L.O.Essen
Key ref:
B.Bieger and L.O.Essen (2001). Structural analysis of adenylate cyclases from Trypanosoma brucei in their monomeric state. EMBO J, 20, 433-445. PubMed id: 11157750 DOI: 10.1093/emboj/20.3.433
Date:
25-Sep-00     Release date:   28-Feb-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q99280  (CY43_TRYBB) -  Receptor-type adenylate cyclase GRESAG 4.3
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1229 a.a.
231 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.4.6.1.1  - Adenylate cyclase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP = 3',5'-cyclic AMP + diphosphate
ATP
 = 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!
  Biological process     cyclic nucleotide biosynthetic process   1 term 
  Biochemical function     phosphorus-oxygen lyase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1093/emboj/20.3.433 EMBO J 20:433-445 (2001)
PubMed id: 11157750  
 
 
Structural analysis of adenylate cyclases from Trypanosoma brucei in their monomeric state.
B.Bieger, L.O.Essen.
 
  ABSTRACT  
 
Cyclic AMP is a major trigger of the differentiation process of Trypanosoma brucei, a bloodstream parasite causing sleeping sickness. Its generation in trypanosomes is accomplished by a unique battery of membrane-bound adenylate cyclases (ACs). We have determined the high-resolution X-ray structures of the catalytic domains of two trypanosomal ACs (tACs), GRESAG4.1 and GRESAG4.3. The tAC domains are structurally highly related to the AC domains of higher eukaryotes, but also comprise a highly conserved structural element near the active site, the Delta-subdomain. A cavity below the Delta-subdomain might correspond to an allosteric regulator site as indicated by the stereospecific binding of a single (2S,3S)-1,4- dimercapto-2,3-butanediol molecule. In three different crystal forms, the tAC domains are exclusively observed in a monomeric, catalytically inactive state. Biochemical analysis and the mutagenesis profile of GRESAG4.1 confirmed a common catalytic mechanism of tACs that involves transient dimerization of the AC domain. A low dimerization tendency might play a regulatory role in T. brucei if the activation of tACs is similarly driven by ligand-induced dimerization as in membrane-bound guanylate cyclases.
 
  Selected figure(s)  
 
Figure 3.
Figure 3 The dimerization of tACs. (A) Model of the tAC dimer as shown from the dorsal (left) and the ventral site (right). Whereas the ventral site is blocked by the pairing of the arm regions (purple), the dorsal site allows substrate access as indicated by ATP molecules occupying both active sites (CPK models). (B) Structural comparison between the arm region of GRESAG4.1 (purple), the C1 (yellow) and C2 domain (blue). The inlay shows the sequence divergence between tACs and other nucleotidyl cyclases in this region. 		Figure 4.
Figure 4 The catalytic surface of tACs. (A) Superposition of GRESAG4.1 (orange, sulfate), GRESAG4.3 (purple, magnesium) and the mammalian C1A domain (blue, metal centers green, ATP S) along the active site surface. (B) Model for the binding of ATP (CPK model) to the catalytic surface of a tAC monomer (green). (C) Binding of a sulfate anion (sticks) to the catalytic surface of GRESAG4.1. (D) Magnesium binding site in the monomeric form of GRESAG4.3. The coordination sphere of the magnesium ion (blue) consists of two conserved aspartates and four water ligands. Putative H-bonds are shown as dotted lines.
 
  The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2001, 20, 433-445) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21223322 M.K.Gould, and H.P.de Koning (2011).
Cyclic-nucleotide signalling in protozoa.
  FEMS Microbiol Rev, 35, 515-541.  
18247345 D.Bandyopadhyay, and E.L.Mehler (2008).
Quantitative expression of protein heterogeneity: Response of amino acid side chains to their local environment.
  Proteins, 72, 646-659.  
17574552 P.Rohloff, and R.Docampo (2008).
A contractile vacuole complex is involved in osmoregulation in Trypanosoma cruzi.
  Exp Parasitol, 118, 17-24.  
18509460 R.D.Emes, and Z.Yang (2008).
Duplicated paralogous genes subject to positive selection in the genome of Trypanosoma brucei.
  PLoS ONE, 3, e2295.  
16002394 C.Steegborn, T.N.Litvin, K.C.Hess, A.B.Capper, R.Taussig, J.Buck, L.R.Levin, and H.Wu (2005).
A novel mechanism for adenylyl cyclase inhibition from the crystal structure of its complex with catechol estrogen.
  J Biol Chem, 280, 31754-31759.
PDB code: 2bw7
15689969 J.J.Tesmer (2005).
A seminal study of soluble adenylyl cyclase.
  Nat Struct Mol Biol, 12, 7-8.  
15955067 L.I.Castro, C.Hermsen, J.E.Schultz, and J.U.Linder (2005).
Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selection.
  FEBS J, 272, 3085-3092.  
16027112 L.M.Iyer, E.V.Koonin, D.D.Leipe, and L.Aravind (2005).
Origin and evolution of the archaeo-eukaryotic primase superfamily and related palm-domain proteins: structural insights and new members.
  Nucleic Acids Res, 33, 3875-3896.  
16164760 M.Parsons, E.A.Worthey, P.N.Ward, and J.C.Mottram (2005).
Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi.
  BMC Genomics, 6, 127.  
15858265 R.Caliandro, B.Carrozzini, G.L.Cascarano, L.De Caro, C.Giacovazzo, and D.Siliqi (2005).
Phasing at resolution higher than the experimental resolution.
  Acta Crystallogr D Biol Crystallogr, 61, 556-565.  
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
15719022 Y.Shen, N.L.Zhukovskaya, Q.Guo, J.Florián, and W.J.Tang (2005).
Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor.
  EMBO J, 24, 929-941.
PDB codes: 1xfu 1xfv 1xfw 1xfx 1xfy 1xfz 1y0v
14747729 A.D.Ketkar, A.R.Shenoy, M.M.Kesavulu, S.S.Visweswariah, and K.Suguna (2004).
Purification, crystallization and preliminary X-ray diffraction analysis of the catalytic domain of adenylyl cyclase Rv1625c from Mycobacterium tuberculosis.
  Acta Crystallogr D Biol Crystallogr, 60, 371-373.  
18629044 A.R.Shenoy, K.Sivakumar, A.Krupa, N.Srinivasan, and S.S.Visweswariah (2004).
A Survey of Nucleotide Cyclases in Actinobacteria: Unique Domain Organization and Expansion of the Class III Cyclase Family in Mycobacterium tuberculosis.
  Comp Funct Genomics, 5, 17-38.  
15165228 D.A.Baker, and J.M.Kelly (2004).
Structure, function and evolution of microbial adenylyl and guanylyl cyclases.
  Mol Microbiol, 52, 1229-1242.  
14718564 S.Saran, and P.Schaap (2004).
Adenylyl cyclase G is activated by an intramolecular osmosensor.
  Mol Biol Cell, 15, 1479-1486.  
12668669 D.K.Muhia, C.A.Swales, U.Eckstein-Ludwig, S.Saran, S.D.Polley, J.M.Kelly, P.Schaap, S.Krishna, and D.A.Baker (2003).
Multiple splice variants encode a novel adenylyl cyclase of possible plastid origin expressed in the sexual stage of the malaria parasite Plasmodium falciparum.
  J Biol Chem, 278, 22014-22022.  
11856299 C.Gu, J.J.Cali, and D.M.Cooper (2002).
Dimerization of mammalian adenylate cyclases.
  Eur J Biochem, 269, 413-421.  
11970848 D.J.Steenkamp (2002).
Trypanosomal antioxidants and emerging aspects of redox regulation in the trypanosomatids.
  Antioxid Redox Signal, 4, 105-121.  
11772023 I.Sokal, A.Alekseev, W.Baehr, F.Haeseleer, and K.Palczewski (2002).
Soluble fusion proteins between single transmembrane photoreceptor guanylyl cyclases and their activators.
  Biochemistry, 41, 251-257.  
11500361 J.Roelofs, M.Meima, P.Schaap, and P.J.Van Haastert (2001).
The Dictyostelium homologue of mammalian soluble adenylyl cyclase encodes a guanylyl cyclase.
  EMBO J, 20, 4341-4348.  
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.