PDBsum entry 2c8l

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Hydrolase PDB id
Jmol PyMol
Protein chain
994 a.a. *
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Crystal structure of (sr) calcium-atpase e2(tg) form
Structure: Sarcoplasmic/endoplasmic reticulum calcium atpase chain: a. Synonym: calcium pump 1, endoplasmic reticulum class 1/2 ca atpas, calcium-transporting atpase sarcoplasmic reticulum ca(2+)-atpase 1, fast twitch skeletal muscle isoform. Ec:
Source: Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Organ: muscle. Tissue: fast twitch skeletal muscle
3.10Å     R-factor:   0.249     R-free:   0.306
Authors: A.M.Jensen,T.L.Sorensen,C.Olesen,J.V.Moller, P.Nissen
Key ref:
A.M.Jensen et al. (2006). Modulatory and catalytic modes of ATP binding by the calcium pump. EMBO J, 25, 2305-2314. PubMed id: 16710301 DOI: 10.1038/sj.emboj.7601135
06-Dec-05     Release date:   13-Jun-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P04191  (AT2A1_RABIT) -  Sarcoplasmic/endoplasmic reticulum calcium ATPase 1
1001 a.a.
994 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.  - Calcium-transporting ATPase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + H2O + Ca2+(Side 1) = ADP + phosphate + Ca2+(Side 2)
+ H(2)O
+ Ca(2+)(Side 1)
+ phosphate
+ Ca(2+)(Side 2)
      Cofactor: Mg(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   6 terms 
  Biological process     transport   6 terms 
  Biochemical function     nucleotide binding     6 terms  


DOI no: 10.1038/sj.emboj.7601135 EMBO J 25:2305-2314 (2006)
PubMed id: 16710301  
Modulatory and catalytic modes of ATP binding by the calcium pump.
A.M.Jensen, T.L.Sørensen, C.Olesen, J.V.Møller, P.Nissen.
We present crystal structures of the calcium-free E2 state of the sarcoplasmic reticulum Ca2+ -ATPase, stabilized by the inhibitor thapsigargin and the ATP analog AMPPCP. The structures allow us to describe the ATP binding site in a modulatory mode uncoupled from the Asp351 phosphorylation site. The Glu439 side chain interacts with AMPPCP via an Mg2+ ion in accordance with previous Fe2+ -cleavage studies implicating this residue in the ATPase cycle and in magnesium binding. Functional data on Ca2+ mediated activation indicate that the crystallized state represents an initial stage of ATP modulated deprotonation of E2, preceding the binding of Ca2+ ions in the membrane from the cytoplasmic side. We propose a mechanism of Ca2+ activation of phosphorylation leading directly from the compact E2-ATP form to the Ca2E1-ATP state. In addition, a role of Glu439 in ATP modulation of other steps of the functional cycle is suggested.
  Selected figure(s)  
Figure 3.
Figure 3 Comparison of the modulatory and the catalytic ATP binding site in SERCA. (A) The modulatory ATP binding site in the H[n]E2(Tg)-AMPPCP structure; compared with (B) the Ca[2]E1-ADP:AlF[4]^- structure. The N and P domain are shown in red and blue cartoon with important residues, involved in ATP binding, shown in ball-and-stick representation. The A domain is excluded for clarity. The ATP-like ligands, AMPPCP or ADP:AlF[4]^- are shown in ball-and-stick and the Mg^2+ ions at sites I and II as cyan spheres. The phosphorylation site is inactive in (A) corresponding to the Ca^2+-free state, whereas it is occluded in (B) corresponding to the occluded Ca^2+-bound state.
Figure 6.
Figure 6 Conformational changes upon Ca^2+ binding to nucleotide bound ATPase. (A) Overall representation of H[n]E2(Tg)-AMPPCP structure shown in gray cartoon with cylindrical helices, and with the M4 helix colored blue. (B) Close-up view of the Ca^2+ binding site with H[n]E2(Tg)-AMPPCP form (blue) superpositioned (on residues 800–994) on the Ca[2]E1-ADP:AlF[4]^- form (orange). (C) Overall representation of Ca[2]E1-ADP:AlF[4]^- corresponding to (A), but with the M4 helix shown in orange. In all figures, the nucleotide is shown in green ball-and-stick representation, Ca^2+ ions are shown as green spheres and key residues involved in Ca^2+ binding in ball-and-stick representation with blue (E2) and orange (E1).
  The above figures are reprinted by permission from Macmillan Publishers Ltd: EMBO J (2006, 25, 2305-2314) copyright 2006.  
  Figures were selected by an automated process.  

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
21179061 J.P.Morth, B.P.Pedersen, M.J.Buch-Pedersen, J.P.Andersen, B.Vilsen, M.G.Palmgren, and P.Nissen (2011).
A structural overview of the plasma membrane Na+,K+-ATPase and H+-ATPase ion pumps.
  Nat Rev Mol Cell Biol, 12, 60-70.  
21396942 K.Walldén, and P.Nordlund (2011).
Structural Basis for the Allosteric Regulation and Substrate Recognition of Human Cytosolic 5'-Nucleotidase II.
  J Mol Biol, 408, 684-696.
PDB codes: 2xcv 2xcw 2xcx 2xjb 2xjc 2xjd 2xje 2xjf
21556058 Y.Sonntag, M.Musgaard, C.Olesen, B.Schiøtt, J.V.Møller, P.Nissen, and L.Thøgersen (2011).
Mutual adaptation of a membrane protein and its lipid bilayer during conformational changes.
  Nat Commun, 2, 304.
PDB code: 2yfy
20177054 J.H.Clark, N.P.Kinnear, S.Kalujnaia, G.Cramb, S.Fleischer, L.H.Jeyakumar, F.Wuytack, and A.M.Evans (2010).
Identification of functionally segregated sarcoplasmic reticulum calcium stores in pulmonary arterial smooth muscle.
  J Biol Chem, 285, 13542-13549.  
20528919 J.T.Tuusa, T.T.Leskelä, and U.E.Petäjä-Repo (2010).
Human delta opioid receptor biogenesis is regulated via interactions with SERCA2b and calnexin.
  FEBS J, 277, 2815-2829.  
20809990 J.V.Møller, C.Olesen, A.M.Winther, and P.Nissen (2010).
The sarcoplasmic Ca2+-ATPase: design of a perfect chemi-osmotic pump.
  Q Rev Biophys, 43, 501-566.  
20634056 M.Bublitz, H.Poulsen, J.P.Morth, and P.Nissen (2010).
In and out of the cation pumps: P-type ATPase structure revisited.
  Curr Opin Struct Biol, 20, 431-439.  
20483338 M.Khalid, F.Cornelius, and R.J.Clarke (2010).
Dual mechanisms of allosteric acceleration of the Na(+),K(+)-ATPase by ATP.
  Biophys J, 98, 2290-2298.  
20813948 M.Rottmann, C.McNamara, B.K.Yeung, M.C.Lee, B.Zou, B.Russell, P.Seitz, D.M.Plouffe, N.V.Dharia, J.Tan, S.B.Cohen, K.R.Spencer, G.E.González-Páez, S.B.Lakshminarayana, A.Goh, R.Suwanarusk, T.Jegla, E.K.Schmitt, H.P.Beck, R.Brun, F.Nosten, L.Renia, V.Dartois, T.H.Keller, D.A.Fidock, E.A.Winzeler, and T.T.Diagana (2010).
Spiroindolones, a potent compound class for the treatment of malaria.
  Science, 329, 1175-1180.  
  20100892 S.Meier, N.N.Tavraz, K.L.Dürr, and T.Friedrich (2010).
Hyperpolarization-activated inward leakage currents caused by deletion or mutation of carboxy-terminal tyrosines of the Na+/K+-ATPase {alpha} subunit.
  J Gen Physiol, 135, 115-134.  
21098671 Y.Sugita, M.Ikeguchi, and C.Toyoshima (2010).
Relationship between Ca2+-affinity and shielding of bulk water in the Ca2+-pump from molecular dynamics simulations.
  Proc Natl Acad Sci U S A, 107, 21465-21469.  
18986966 D.C.Gadsby, A.Takeuchi, P.Artigas, and N.Reyes (2009).
Review. Peering into an ATPase ion pump with single-channel recordings.
  Philos Trans R Soc Lond B Biol Sci, 364, 229-238.  
18957371 J.P.Morth, H.Poulsen, M.S.Toustrup-Jensen, V.R.Schack, J.Egebjerg, J.P.Andersen, B.Vilsen, and P.Nissen (2009).
The structure of the Na+,K+-ATPase and mapping of isoform differences and disease-related mutations.
  Philos Trans R Soc Lond B Biol Sci, 364, 217-227.  
19525226 M.González-Guerrero, D.Hong, and J.M.Argüello (2009).
Chaperone-mediated Cu+ Delivery to Cu+ Transport ATPases: REQUIREMENT OF NUCLEOTIDE BINDING.
  J Biol Chem, 284, 20804-20811.  
19751681 M.Kubala, L.Grycova, Z.Lansky, P.Sklenovsky, M.Janovska, M.Otyepka, and J.Teisinger (2009).
Changes in electrostatic surface potential of Na+/K+-ATPase cytoplasmic headpiece induced by cytoplasmic ligand(s) binding.
  Biophys J, 97, 1756-1764.  
19289472 M.Laursen, M.Bublitz, K.Moncoq, C.Olesen, J.V.Møller, H.S.Young, P.Nissen, and J.P.Morth (2009).
Cyclopiazonic Acid Is Complexed to a Divalent Metal Ion When Bound to the Sarcoplasmic Reticulum Ca2+-ATPase.
  J Biol Chem, 284, 13513-13518.
PDB codes: 3fgo 3fpb 3fps
19494845 P.Nissen (2009).
One way for the gastric proton pump.
  EMBO J, 28, 1535-1536.  
19740735 T.Fusca, M.C.Bonza, L.Luoni, S.Meneghelli, C.A.Marrano, and M.I.De Michelis (2009).
Single point mutations in the small cytoplasmic loop of ACA8, a plasma membrane Ca2+-ATPase of Arabidopsis thaliana, generate partially deregulated pumps.
  J Biol Chem, 284, 30881-30888.  
19458722 T.Shinoda, H.Ogawa, F.Cornelius, and C.Toyoshima (2009).
Crystal structure of the sodium-potassium pump at 2.4 A resolution.
  Nature, 459, 446-450.
PDB code: 2zxe
19628462 X.Liu, T.Daiho, K.Yamasaki, G.Wang, S.Danko, and H.Suzuki (2009).
Roles of interaction between actuator and nucleotide binding domains of sarco(endo)plasmic reticulum Ca(2+)-ATPase as revealed by single and swap mutational analyses of serine 186 and glutamate 439.
  J Biol Chem, 284, 25190-25198.  
18356161 A.Marchand, A.M.Winther, P.J.Holm, C.Olesen, C.Montigny, B.Arnou, P.Champeil, J.D.Clausen, B.Vilsen, J.P.Andersen, P.Nissen, C.Jaxel, J.V.Møller, and M.le Maire (2008).
Crystal structure of D351A and P312A mutant forms of the mammalian sarcoplasmic reticulum Ca(2+) -ATPase reveals key events in phosphorylation and Ca(2+) release.
  J Biol Chem, 283, 14867-14882.  
17945510 G.B.Hu, W.J.Rice, S.Dröse, K.Altendorf, and D.L.Stokes (2008).
Three-dimensional structure of the KdpFABC complex of Escherichia coli by electron tomography of two-dimensional crystals.
  J Struct Biol, 161, 411-418.  
17993458 G.Inesi, D.Lewis, C.Toyoshima, A.Hirata, and Meis (2008).
Conformational fluctuations of the Ca2+-ATPase in the native membrane environment. Effects of pH, temperature, catalytic substrates, and thapsigargin.
  J Biol Chem, 283, 1189-1196.  
18252706 I.Moreno, L.Norambuena, D.Maturana, M.Toro, C.Vergara, A.Orellana, A.Zurita-Silva, and V.R.Ordenes (2008).
AtHMA1 is a thapsigargin-sensitive Ca2+/heavy metal pump.
  J Biol Chem, 283, 9633-9641.  
17890386 J.Andersson, K.Hauser, E.L.Karjalainen, and A.Barth (2008).
Protonation and hydrogen bonding of Ca2+ site residues in the E2P phosphoenzyme intermediate of sarcoplasmic reticulum Ca2+-ATPase studied by a combination of infrared spectroscopy and electrostatic calculations.
  Biophys J, 94, 600-611.  
18930923 J.D.Clausen, D.B.McIntosh, D.G.Woolley, and J.P.Andersen (2008).
Critical Interaction of Actuator Domain Residues Arginine 174, Isoleucine 188, and Lysine 205 with Modulatory Nucleotide in Sarcoplasmic Reticulum Ca2+-ATPase.
  J Biol Chem, 283, 35703-35714.  
18055532 M.Esmann, N.U.Fedosova, and D.Marsh (2008).
Osmotic stress and viscous retardation of the Na,K-ATPase ion pump.
  Biophys J, 94, 2767-2776.  
18768923 P.R.Stabach, P.Devarajan, M.C.Stankewich, S.Bannykh, and J.S.Morrow (2008).
Ankyrin facilitates intracellular trafficking of alpha1-Na+-K+-ATPase in polarized cells.
  Am J Physiol Cell Physiol, 295, C1202-C1214.  
18562314 Y.Hatori, A.Hirata, C.Toyoshima, D.Lewis, R.Pilankatta, and G.Inesi (2008).
Intermediate phosphorylation reactions in the mechanism of ATP utilization by the copper ATPase (CopA) of Thermotoga maritima.
  J Biol Chem, 283, 22541-22549.  
17615289 A.Fibich, K.Janko, and H.J.Apell (2007).
Kinetics of proton binding to the sarcoplasmic reticulum Ca-ATPase in the E1 state.
  Biophys J, 93, 3092-3104.  
18058007 A.P.Einholm, J.P.Andersen, and B.Vilsen (2007).
Roles of transmembrane segment M1 of Na(+),K (+)-ATPase and Ca (2+)-ATPase, the gatekeeper and the pivot.
  J Bioenerg Biomembr, 39, 357-366.  
18075595 B.P.Pedersen, M.J.Buch-Pedersen, J.P.Morth, M.G.Palmgren, and P.Nissen (2007).
Crystal structure of the plasma membrane proton pump.
  Nature, 450, 1111-1114.
PDB code: 3b8c
18075584 C.Olesen, M.Picard, A.M.Winther, C.Gyrup, J.P.Morth, C.Oxvig, J.V.Møller, and P.Nissen (2007).
The structural basis of calcium transport by the calcium pump.
  Nature, 450, 1036-1042.
PDB codes: 3b9b 3b9r 3ba6
18077416 C.Toyoshima, Y.Norimatsu, S.Iwasawa, T.Tsuda, and H.Ogawa (2007).
How processing of aspartylphosphate is coupled to lumenal gating of the ion pathway in the calcium pump.
  Proc Natl Acad Sci U S A, 104, 19831-19836.
PDB codes: 2zbe 2zbf 2zbg
17904096 E.L.Karjalainen, K.Hauser, and A.Barth (2007).
Proton paths in the sarcoplasmic reticulum Ca(2+) -ATPase.
  Biochim Biophys Acta, 1767, 1310-1318.  
17573037 G.Guerra, V.V.Petrov, K.E.Allen, M.Miranda, J.P.Pardo, and C.W.Slayman (2007).
Role of transmembrane segment M8 in the biogenesis and function of yeast plasma-membrane H(+)-ATPase.
  Biochim Biophys Acta, 1768, 2383-2392.  
17901055 G.R.Corradi, and H.P.Adamo (2007).
Intramolecular fluorescence resonance energy transfer between fused autofluorescent proteins reveals rearrangements of the N- and C-terminal segments of the plasma membrane Ca2+ pump involved in the activation.
  J Biol Chem, 282, 35440-35448.  
17504757 J.D.Clausen, D.B.McIntosh, A.N.Anthonisen, D.G.Woolley, B.Vilsen, and J.P.Andersen (2007).
ATP-binding modes and functionally important interdomain bonds of sarcoplasmic reticulum Ca2+-ATPase revealed by mutation of glycine 438, glutamate 439, and arginine 678.
  J Biol Chem, 282, 20686-20697.  
17481903 J.J.Lacapère, E.Pebay-Peyroula, J.M.Neumann, and C.Etchebest (2007).
Determining membrane protein structures: still a challenge!
  Trends Biochem Sci, 32, 259-270.  
17938423 K.Hauser, and A.Barth (2007).
Side-chain protonation and mobility in the sarcoplasmic reticulum Ca2+-ATPase: implications for proton countertransport and Ca2+ release.
  Biophys J, 93, 3259-3270.  
17259168 K.Moncoq, C.A.Trieber, and H.S.Young (2007).
The molecular basis for cyclopiazonic acid inhibition of the sarcoplasmic reticulum calcium pump.
  J Biol Chem, 282, 9748-9757.
PDB codes: 2o9j 2oa0
17389383 M.Takahashi, Y.Kondou, and C.Toyoshima (2007).
Interdomain communication in calcium pump as revealed in the crystal structures with transmembrane inhibitors.
  Proc Natl Acad Sci U S A, 104, 5800-5805.
PDB codes: 2ear 2eat 2eau 4ycl
17105196 G.Inesi, D.Lewis, H.Ma, A.Prasad, and C.Toyoshima (2006).
Concerted conformational effects of Ca2+ and ATP are required for activation of sequential reactions in the Ca2+ ATPase (SERCA) catalytic cycle.
  Biochemistry, 45, 13769-13778.  
17557166 P.Purhonen, K.Thomsen, A.B.Maunsbach, and H.Hebert (2006).
Association of renal Na,K-ATPase alpha-subunit with the beta- and gamma-subunits based on cryoelectron microscopy.
  J Membr Biol, 214, 139-146.  
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.