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PDBsum entry 1wc1

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protein ligands metals Protein-protein interface(s) links
Lyase PDB id
1wc1
Jmol
Contents
Protein chains
197 a.a. *
Ligands
TAT ×3
Metals
_MG ×6
Waters ×385
* Residue conservation analysis
PDB id:
1wc1
Name: Lyase
Title: Soluble adenylyl cyclase cyac from s. Platensis in complex with rp-atpalphas
Structure: Adenylate cyclase. Chain: a, b, c. Fragment: catalytic domain, residues 998-1202. Synonym: soluble adenylyl cyclase cyac. Engineered: yes
Source: Spirulina platensis. Organism_taxid: 118562. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
Resolution:
1.93Å     R-factor:   0.198     R-free:   0.229
Authors: C.Steegborn,T.N.Litvin,L.R.Levin,J.Buck,H.Wu
Key ref:
C.Steegborn et al. (2005). Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment. Nat Struct Mol Biol, 12, 32-37. PubMed id: 15619637 DOI: 10.1038/nsmb880
Date:
06-Nov-04     Release date:   20-Dec-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O32393  (O32393_SPIPL) -  Adenylate cyclase
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1202 a.a.
197 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: 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 = TAT)
matches with 93.75% 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!
  Biological process     intracellular signal transduction   2 terms 
  Biochemical function     phosphorus-oxygen lyase activity     1 term  

 

 
    reference    
 
 
DOI no: 10.1038/nsmb880 Nat Struct Mol Biol 12:32-37 (2005)
PubMed id: 15619637  
 
 
Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment.
C.Steegborn, T.N.Litvin, L.R.Levin, J.Buck, H.Wu.
 
  ABSTRACT  
 
In an evolutionarily conserved signaling pathway, 'soluble' adenylyl cyclases (sACs) synthesize the ubiquitous second messenger cyclic adenosine 3',5'-monophosphate (cAMP) in response to bicarbonate and calcium signals. Here, we present crystal structures of a cyanobacterial sAC enzyme in complex with ATP analogs, calcium and bicarbonate, which represent distinct catalytic states of the enzyme. The structures reveal that calcium occupies the first ion-binding site and directly mediates nucleotide binding. The single ion-occupied, nucleotide-bound state defines a novel, open adenylyl cyclase state. In contrast, bicarbonate increases the catalytic rate by inducing marked active site closure and recruiting a second, catalytic ion. The phosphates of the bound substrate analogs are rearranged, which would facilitate product formation and release. The mechanisms of calcium and bicarbonate sensing define a reaction pathway involving active site closure and metal recruitment that may be universal for class III cyclases.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Conformational states and comparison of AC enzymes. (a) Structure-based sequence alignment of bicarbonate responsive sAC enzymes and the G protein -regulated tmAC domains VC[1] and IIC[2] (PDB entry 1AZS). Secondary structure elements of sAC and IIC[2] are indicated on top and bottom, respectively. Ion-binding residues ( ) and residues binding the substrate (^) or the transition state ( ) are labeled (filled and empty symbols label C[1] and C[2] residues, respectively). Thr1139^* and the insertion characteristic for sAC enzymes are indicated ( ). Conserved amino acids are shaded yellow, and residues with conserved physicochemical properties are shaded red. (b) Overlay of the sAC - , -Me-ATP structure (open state, darkest gray, with 1 helix and 7 - 8 loop in blue), the sAC -Rp-ATP S complex (partially closed, middle gray and red), and the bicarbonate-soaked Rp-ATP S structure (closed, lightest gray and yellow). Structures were superimposed on sAC - , -Me-ATP by optimizing positional agreement for residues 1014 -1018, 1056 -1065, 1117 -1126 and 1143 -1167 in both subunits. (c) sAC active site in complex with Rp-ATP S and two magnesium ions, with the two monomers colored red and blue, respectively. The dashed lines indicate the octahedral coordination of the ions through the ATP analog, protein residues and one and two water molecules (gold spheres), respectively. The 2F[o] - F[c] omit electron density for the ligands was contoured at 1.1 . In its tmAC complex, P of Rp-ATP S was modeled differently but with limited electron density for the ribose and its link to the P 16, and we speculate that this density might also be interpretable with the inhibitor conformation observed here for its sAC complex.
Figure 4.
Figure 4. Model for catalysis by class III nucleotidyl cyclases. The model for catalysis (bottom pathway) is based on the conformational changes observed with the sAC -substrate analog complexes (top). The arrows at 1 and 7 - 8 indicate the movements undergone by these protein parts. The individual catalytic states (open, intermediate and closed) are extrapolated from the different sAC structures presented in the text, with the protein conformation of the sAC -Rp-ATP S complex being a speculative approximate intermediate state.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Mol Biol (2005, 12, 32-37) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21544217 J.Buck, and L.R.Levin (2011).
Physiological Sensing of Carbon Dioxide/Bicarbonate/pH via Cyclic Nucleotide Signaling.
  Sensors Basel Sensors, 11, 2112-2128.  
20683624 M.Tresguerres, J.Buck, and L.R.Levin (2010).
Physiological carbon dioxide, bicarbonate, and pH sensing.
  Pflugers Arch, 460, 953-964.  
21124988 R.A.Hall, L.De Sordi, D.M.Maccallum, H.Topal, R.Eaton, J.W.Bloor, G.K.Robinson, L.R.Levin, J.Buck, Y.Wang, N.A.Gow, C.Steegborn, and F.A.Mühlschlegel (2010).
CO(2) acts as a signalling molecule in populations of the fungal pathogen Candida albicans.
  PLoS Pathog, 6, e1001193.  
19331426 D.Guo, J.J.Zhang, and X.Y.Huang (2009).
Stimulation of guanylyl cyclase-D by bicarbonate.
  Biochemistry, 48, 4417-4422.  
19922557 L.Mann, E.Heldman, Y.Bersudsky, S.F.Vatner, Y.Ishikawa, O.Almog, R.H.Belmaker, and G.Agam (2009).
Inhibition of specific adenylyl cyclase isoforms by lithium and carbamazepine, but not valproate, may be related to their antidepressant effect.
  Bipolar Disord, 11, 885-896.  
19181845 L.Sun, H.Wang, J.Hu, J.Han, H.Matsunami, and M.Luo (2009).
Guanylyl cyclase-D in the olfactory CO2 neurons is activated by bicarbonate.
  Proc Natl Acad Sci U S A, 106, 2041-2046.  
19546222 M.T.Branham, M.A.Bustos, G.A.De Blas, H.Rehmann, V.E.Zarelli, C.L.Treviño, A.Darszon, L.S.Mayorga, and C.N.Tomes (2009).
Epac activates the small G proteins Rap1 and Rab3A to achieve exocytosis.
  J Biol Chem, 284, 24825-24839.  
19008230 P.D.Townsend, P.M.Holliday, S.Fenyk, K.C.Hess, M.A.Gray, D.R.Hodgson, and M.J.Cann (2009).
Stimulation of Mammalian G-protein-responsive Adenylyl Cyclases by Carbon Dioxide.
  J Biol Chem, 284, 784-791.  
19254571 R.Acin-Perez, E.Salazar, M.Kamenetsky, J.Buck, L.R.Levin, and G.Manfredi (2009).
Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation.
  Cell Metab, 9, 265-276.  
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.  
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
19560485 W.J.Tang, and Q.Guo (2009).
The adenylyl cyclase activity of anthrax edema factor.
  Mol Aspects Med, 30, 423-430.  
18840690 A.Rauch, M.Leipelt, M.Russwurm, and C.Steegborn (2008).
Crystal structure of the guanylyl cyclase Cya2.
  Proc Natl Acad Sci U S A, 105, 15720-15725.
PDB code: 2w01
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.  
19054664 J.U.Linder, and J.E.Schultz (2008).
Versatility of signal transduction encoded in dimeric adenylyl cyclases.
  Curr Opin Struct Biol, 18, 667-672.  
  17591988 A.Schmid, Z.Sutto, M.C.Nlend, G.Horvath, N.Schmid, J.Buck, L.R.Levin, G.E.Conner, N.Fregien, and M.Salathe (2007).
Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP.
  J Gen Physiol, 130, 99.  
17697997 P.Wassmann, C.Chan, R.Paul, A.Beck, H.Heerklotz, U.Jenal, and T.Schirmer (2007).
Structure of BeF3- -modified response regulator PleD: implications for diguanylate cyclase activation, catalysis, and feedback inhibition.
  Structure, 15, 915-927.
PDB code: 2v0n
16250004 J.A.Chaloupka, S.A.Bullock, V.Iourgenko, L.R.Levin, and J.Buck (2006).
Autoinhibitory regulation of soluble adenylyl cyclase.
  Mol Reprod Dev, 73, 361-368.  
16760311 M.K.Ashby, and J.Houmard (2006).
Cyanobacterial two-component proteins: structure, diversity, distribution, and evolution.
  Microbiol Mol Biol Rev, 70, 472-509.  
16407249 M.T.Branham, L.S.Mayorga, and C.N.Tomes (2006).
Calcium-induced acrosomal exocytosis requires cAMP acting through a protein kinase A-independent, Epac-mediated pathway.
  J Biol Chem, 281, 8656-8666.  
16269411 M.T.Naik, N.Suree, U.Ilangovan, C.K.Liew, W.Thieu, D.O.Campbell, J.J.Clemens, M.E.Jung, and R.T.Clubb (2006).
Staphylococcus aureus Sortase A transpeptidase. Calcium promotes sorting signal binding by altering the mobility and structure of an active site loop.
  J Biol Chem, 281, 1817-1826.  
16619222 U.B.Kaupp, E.Hildebrand, and I.Weyand (2006).
Sperm chemotaxis in marine invertebrates--molecules and mechanisms.
  J Cell Physiol, 208, 487-494.  
17045514 Y.S.Bahn, and F.A.Mühlschlegel (2006).
CO2 sensing in fungi and beyond.
  Curr Opin Microbiol, 9, 572-578.  
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.  
16138079 Q.Guo, Y.Shen, Y.S.Lee, C.S.Gibbs, M.Mrksich, and W.J.Tang (2005).
Structural basis for the interaction of Bordetella pertussis adenylyl cyclase toxin with calmodulin.
  EMBO J, 24, 3190-3201.
PDB codes: 1yrt 1yru 1zot 2col
15995223 S.Masuda, and T.A.Ono (2005).
Adenylyl cyclase activity of Cya1 from the cyanobacterium Synechocystis sp. strain PCC 6803 is inhibited by bicarbonate.
  J Bacteriol, 187, 5032-5035.  
16303561 T.Klengel, W.J.Liang, J.Chaloupka, C.Ruoff, K.Schröppel, J.R.Naglik, S.E.Eckert, E.G.Mogensen, K.Haynes, M.F.Tuite, L.R.Levin, J.Buck, and F.A.Mühlschlegel (2005).
Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence.
  Curr Biol, 15, 2021-2026.  
16045612 Y.L.Guo, U.Kurz, A.Schultz, J.U.Linder, D.Dittrich, C.Keller, S.Ehlers, P.Sander, and J.E.Schultz (2005).
Interaction of Rv1625c, a mycobacterial class IIIa adenylyl cyclase, with a mammalian congener.
  Mol Microbiol, 57, 667-677.  
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.