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PDBsum entry 1gsf

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protein ligands Protein-protein interface(s) links
Transferase (glutathione) PDB id
1gsf
Jmol
Contents
Protein chain
221 a.a. *
Ligands
EAA ×4
Waters ×150
* Residue conservation analysis
PDB id:
1gsf
Name: Transferase (glutathione)
Title: Glutathione transferase a1-1 complexed with ethacrynic acid
Structure: Glutathione transferase a1-1. Chain: a, b, c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: liver. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.229     R-free:   0.261
Authors: G.L'Hermite,I.Sinning,A.D.Cameron,T.A.Jones
Key ref:
A.D.Cameron et al. (1995). Structural analysis of human alpha-class glutathione transferase A1-1 in the apo-form and in complexes with ethacrynic acid and its glutathione conjugate. Structure, 3, 717-727. PubMed id: 8591048 DOI: 10.1016/S0969-2126(01)00206-4
Date:
09-Jun-95     Release date:   15-Sep-95    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P08263  (GSTA1_HUMAN) -  Glutathione S-transferase A1
Seq:
Struc:
222 a.a.
221 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.5.1.18  - Glutathione transferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: RX + glutathione = HX + R-S-glutathione
RX
+ glutathione
= HX
+ R-S-glutathione
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   3 terms 
  Biological process     metabolic process   6 terms 
  Biochemical function     transferase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S0969-2126(01)00206-4 Structure 3:717-727 (1995)
PubMed id: 8591048  
 
 
Structural analysis of human alpha-class glutathione transferase A1-1 in the apo-form and in complexes with ethacrynic acid and its glutathione conjugate.
A.D.Cameron, I.Sinning, G.L'Hermite, B.Olin, P.G.Board, B.Mannervik, T.A.Jones.
 
  ABSTRACT  
 
BACKGROUND: Glutathione transferases (GSTs) constitute a family of isoenzymes that catalyze the conjugation of the tripeptide glutathione with a wide variety of hydrophobic compounds bearing an electrophilic functional group. Recently, a number of X-ray structures have been reported which have defined both the glutathione- and the substrate-binding sites in these enzymes. The structure of the glutathione-free enzyme from a mammalian source has not, however, been reported previously. RESULTS: We have solved structures of a human alpha-class GST, isoenzyme A1-1, both in the unliganded form and in complexes with the inhibitor ethacrynic acid and its glutathione conjugate. These structures have been refined to resolutions of 2.5 A, 2.7 A and 2.0 A respectively. Both forms of the inhibitor are clearly present in the associated electron density. CONCLUSIONS: The major differences among the three structures reported here involve the C-terminal alpha-helix, which is a characteristic of the alpha-class enzyme. This helix forms a lid over the active site when the hydrophobic substrate binding site (H-site) is occupied but it is otherwise disordered. Ethacrynic acid appears to bind in a non-productive mode in the absence of the coenzyme glutathione.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Schematic representation of (a) EA and (b) EA-GSH. The glutathione moiety is represented by SG. Figure 1. Schematic representation of (a) EA and (b) EA-GSH. The glutathione moiety is represented by SG.
Figure 7.
Figure 7. Superposition of the EA complex structure on that of the EA–GSH complex showing the difference in the position of the EA moiety. Both orientations of the EA moiety in the EA–GSH complex are shown, with carbon atoms coloured magenta. The carbon atoms belonging to EA in the EA complex have been coloured brown. Protein carbon atoms are coloured yellow for the EA–GSH complex and brown for the EA complex. The ribbon representation of the Cα traces are coloured as in Figure 2 for the EA–GSH complex and blue for the EA complex. The two molecules have been superimposed using a least-squares fit of the Cα atoms of the respective monomers. Figure 7. Superposition of the EA complex structure on that of the EA–GSH complex showing the difference in the position of the EA moiety. Both orientations of the EA moiety in the EA–GSH complex are shown, with carbon atoms coloured magenta. The carbon atoms belonging to EA in the EA complex have been coloured brown. Protein carbon atoms are coloured yellow for the EA–GSH complex and brown for the EA complex. The ribbon representation of the Cα traces are coloured as in [3]Figure 2 for the EA–GSH complex and blue for the EA complex. The two molecules have been superimposed using a least-squares fit of the Cα atoms of the respective monomers.
 
  The above figures are reprinted by permission from Cell Press: Structure (1995, 3, 717-727) copyright 1995.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21428697 A.Oakley (2011).
Glutathione transferases: a structural perspective.
  Drug Metab Rev, 43, 138-151.  
21283550 C.Tuzmen, and B.Erman (2011).
Identification of ligand binding sites of proteins using the gaussian network model.
  PLoS One, 6, e16474.  
  21425928 J.U.Flanagan, and M.L.Smythe (2011).
Sigma-class glutathione transferases.
  Drug Metab Rev, 43, 194-214.  
  21401344 L.M.Balogh, and W.M.Atkins (2011).
Interactions of glutathione transferases with 4-hydroxynonenal.
  Drug Metab Rev, 43, 165-178.  
20085333 L.M.Balogh, I.Le Trong, K.A.Kripps, L.M.Shireman, R.E.Stenkamp, W.Zhang, B.Mannervik, and W.M.Atkins (2010).
Substrate specificity combined with stereopromiscuity in glutathione transferase A4-4-dependent metabolism of 4-hydroxynonenal.
  Biochemistry, 49, 1541-1548.
PDB codes: 3ik7 3ik9
19780048 I.Quesada-Soriano, L.J.Parker, A.Primavera, J.M.Casas-Solvas, A.Vargas-Berenguel, C.Barón, C.J.Morton, A.Paola Mazzetti, M.Lo Bello, M.W.Parker, and L.García-Fuentes (2009).
Influence of the H-site residue 108 on human glutathione transferase P1-1 ligand binding: Structure-thermodynamic relationships and thermal stability.
  Protein Sci, 18, 2454-2470.
PDB codes: 3hjm 3hjo 3hkr
19618965 L.M.Balogh, I.Le Trong, K.A.Kripps, K.Tars, R.E.Stenkamp, B.Mannervik, and W.M.Atkins (2009).
Structural analysis of a glutathione transferase A1-1 mutant tailored for high catalytic efficiency with toxic alkenals.
  Biochemistry, 48, 7698-7704.
PDB codes: 3i69 3i6a
18792041 D.F.Dourado, P.A.Fernandes, B.Mannervik, and M.J.Ramos (2008).
Glutathione transferase: new model for glutathione activation.
  Chemistry, 14, 9591-9598.  
18424441 L.M.Balogh, A.G.Roberts, L.M.Shireman, R.J.Greene, and W.M.Atkins (2008).
The stereochemical course of 4-hydroxy-2-nonenal metabolism by glutathione S-transferases.
  J Biol Chem, 283, 16702-16710.  
18703268 N.Kinsley, Y.Sayed, S.Mosebi, R.N.Armstrong, and H.W.Dirr (2008).
Characterization of the binding of 8-anilinonaphthalene sulfonate to rat class Mu GST M1-1.
  Biophys Chem, 137, 100-104.  
  19662104 X.Ji, A.Pal, R.Kalathur, X.Hu, Y.Gu, J.E.Saavedra, G.S.Buzard, A.Srinivasan, L.K.Keefer, and S.V.Singh (2008).
Structure-Based Design of Anticancer Prodrug PABA/NO.
  Drug Des Devel Ther, 2, 123-130.  
17682821 B.Blanchette, X.Feng, and B.R.Singh (2007).
Marine glutathione S-transferases.
  Mar Biotechnol (NY), 9, 513-542.  
17561509 L.Hou, M.T.Honaker, L.M.Shireman, L.M.Balogh, A.G.Roberts, K.C.Ng, A.Nath, and W.M.Atkins (2007).
Functional promiscuity correlates with conformational heterogeneity in A-class glutathione S-transferases.
  J Biol Chem, 282, 23264-23274.  
16421451 E.Grahn, M.Novotny, E.Jakobsson, A.Gustafsson, L.Grehn, B.Olin, D.Madsen, M.Wahlberg, B.Mannervik, and G.J.Kleywegt (2006).
New crystal structures of human glutathione transferase A1-1 shed light on glutathione binding and the conformation of the C-terminal helix.
  Acta Crystallogr D Biol Crystallogr, 62, 197-207.
PDB codes: 1pkw 1pkz 1pl1 1pl2 1xwg
16154081 F.Angelucci, P.Baiocco, M.Brunori, L.Gourlay, V.Morea, and A.Bellelli (2005).
Insights into the catalytic mechanism of glutathione S-transferase: the lesson from Schistosoma haematobium.
  Structure, 13, 1241-1246.  
15757902 H.W.Dirr, T.Little, D.C.Kuhnert, and Y.Sayed (2005).
A conserved N-capping motif contributes significantly to the stabilization and dynamics of the C-terminal region of class Alpha glutathione S-transferases.
  J Biol Chem, 280, 19480-19487.  
16081649 J.Li, Z.Xia, and J.Ding (2005).
Thioredoxin-like domain of human kappa class glutathione transferase reveals sequence homology and structure similarity to the theta class enzyme.
  Protein Sci, 14, 2361-2369.
PDB code: 1yzx
15640152 M.Perbandt, J.Höppner, C.Betzel, R.D.Walter, and E.Liebau (2005).
Structure of the major cytosolic glutathione S-transferase from the parasitic nematode Onchocerca volvulus.
  J Biol Chem, 280, 12630-12636.
PDB codes: 1tu7 1tu8
16108014 S.Hederos, and L.Baltzer (2005).
Nucleophile selectivity in the acyl transfer reaction of a designed enzyme.
  Biopolymers, 79, 292-299.  
15388865 J.Warwicker (2004).
Improved pKa calculations through flexibility based sampling of a water-dominated interaction scheme.
  Protein Sci, 13, 2793-2805.  
12972411 M.Perbandt, C.Burmeister, R.D.Walter, C.Betzel, and E.Liebau (2004).
Native and inhibited structure of a Mu class-related glutathione S-transferase from Plasmodium falciparum.
  J Biol Chem, 279, 1336-1342.
PDB codes: 1pa3 1q4j
14690442 S.Mosebi, Y.Sayed, J.Burke, and H.W.Dirr (2003).
Residue 219 impacts on the dynamics of the C-terminal region in glutathione transferase A1-1: implications for stability and catalytic and ligandin functions.
  Biochemistry, 42, 15326-15332.  
11889135 A.M.Caccuri, G.Antonini, N.Allocati, C.Di Ilio, F.De Maria, F.Innocenti, M.W.Parker, M.Masulli, M.Lo Bello, P.Turella, G.Federici, and G.Ricci (2002).
GSTB1-1 from Proteus mirabilis: a snapshot of an enzyme in the evolutionary pathway from a redox enzyme to a conjugating enzyme.
  J Biol Chem, 277, 18777-18784.  
11872752 A.S.Johansson, and B.Mannervik (2002).
Active-site residues governing high steroid isomerase activity in human glutathione transferase A3-3.
  J Biol Chem, 277, 16648-16654.  
12211029 I.Le Trong, R.E.Stenkamp, C.Ibarra, W.M.Atkins, and E.T.Adman (2002).
1.3-A resolution structure of human glutathione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site.
  Proteins, 48, 618-627.
PDB codes: 1k3l 1k3o 1k3y
12023294 P.L.Pettersson, A.S.Johansson, and B.Mannervik (2002).
Transmutation of human glutathione transferase A2-2 with peroxidase activity into an efficient steroid isomerase.
  J Biol Chem, 277, 30019-30022.  
11604524 A.J.Oakley, T.Harnnoi, R.Udomsinprasert, K.Jirajaroenrat, A.J.Ketterman, and M.C.Wilce (2001).
The crystal structures of glutathione S-transferases isozymes 1-3 and 1-4 from Anopheles dirus species B.
  Protein Sci, 10, 2176-2185.
PDB codes: 1jlv 1jlw
11297419 B.S.Nieslanik, C.Ibarra, and W.M.Atkins (2001).
The C-terminus of glutathione S-transferase A1-1 is required for entropically-driven ligand binding.
  Biochemistry, 40, 3536-3543.  
11524005 C.Ibarra, B.S.Nieslanik, and W.M.Atkins (2001).
Contribution of aromatic-aromatic interactions to the anomalous pK(a) of tyrosine-9 and the C-terminal dynamics of glutathione S-transferase A1-1.
  Biochemistry, 40, 10614-10624.  
11119643 E.T.Adman, I.Le Trong, R.E.Stenkamp, B.S.Nieslanik, E.C.Dietze, G.Tai, C.Ibarra, and W.M.Atkins (2001).
Localization of the C-terminus of rat glutathione S-transferase A1-1: crystal structure of mutants W21F and W21F/F220Y.
  Proteins, 42, 192-200.
PDB codes: 1ev4 1ev9
10681528 J.Wang, S.Bauman, and R.F.Colman (2000).
Probing subunit interactions in alpha class rat liver glutathione S-transferase with the photoaffinity label glutathionyl S-[4-(succinimidyl)benzophenone].
  J Biol Chem, 275, 5493-5503.  
10900265 L.O.Nilsson, A.Gustafsson, and B.Mannervik (2000).
Redesign of substrate-selectivity determining modules of glutathione transferase A1-1 installs high catalytic efficiency with toxic alkenal products of lipid peroxidation.
  Proc Natl Acad Sci U S A, 97, 9408-9412.  
10883816 M.Ishigai, J.I.Langridge, R.S.Bordoli, and S.J.Gaskell (2000).
Noncovalent associations of glutathione S-transferase and ligands: a study using electrospray quadrupole/time-of-flight mass spectrometry.
  J Am Soc Mass Spectrom, 11, 606-614.  
11027134 Y.Gu, S.V.Singh, and X.Ji (2000).
Residue R216 and catalytic efficiency of a murine class alpha glutathione S-transferase toward benzo[a]pyrene 7(R),8(S)-diol 9(S), 10(R)-epoxide.
  Biochemistry, 39, 12552-12557.
PDB codes: 1f3a 1f3b
10587450 A.Gustafsson, M.Etahadieh, P.Jemth, and B.Mannervik (1999).
The C-terminal region of human glutathione transferase A1-1 affects the rate of glutathione binding and the ionization of the active-site Tyr9.
  Biochemistry, 38, 16268-16275.  
10346919 B.S.Nieslanik, M.J.Dabrowski, R.P.Lyon, and W.M.Atkins (1999).
Stopped-flow kinetic analysis of the ligand-induced coil-helix transition in glutathione S-transferase A1-1: evidence for a persistent denatured state.
  Biochemistry, 38, 6971-6980.  
10569948 H.W.Dirr, and L.A.Wallace (1999).
Role of the C-terminal helix 9 in the stability and ligandin function of class alpha glutathione transferase A1-1.
  Biochemistry, 38, 15631-15640.  
10600132 L.A.Wallace, and H.W.Dirr (1999).
Folding and assembly of dimeric human glutathione transferase A1-1.
  Biochemistry, 38, 16686-16694.  
9665696 A.J.Oakley, M.Lo Bello, G.Ricci, G.Federici, and M.W.Parker (1998).
Evidence for an induced-fit mechanism operating in pi class glutathione transferases.
  Biochemistry, 37, 9912-9917.
PDB codes: 14gs 16gs
9799517 J.M.Stevens, J.A.Hornby, R.N.Armstrong, and H.W.Dirr (1998).
Class sigma glutathione transferase unfolds via a dimeric and a monomeric intermediate: impact of subunit interface on conformational stability in the superfamily.
  Biochemistry, 37, 15534-15541.  
9551553 J.Rossjohn, W.J.McKinstry, A.J.Oakley, D.Verger, J.Flanagan, G.Chelvanayagam, K.L.Tan, P.G.Board, and M.W.Parker (1998).
Human theta class glutathione transferase: the crystal structure reveals a sulfate-binding pocket within a buried active site.
  Structure, 6, 309-322.
PDB codes: 1ljr 2ljr 3ljr
9548764 L.A.Wallace, N.Sluis-Cremer, and H.W.Dirr (1998).
Equilibrium and kinetic unfolding properties of dimeric human glutathione transferase A1-1.
  Biochemistry, 37, 5320-5328.  
9761928 L.N.Patskovska, A.A.Fedorov, Y.V.Patskovsky, S.C.Almo, and I.Listowsky (1998).
Expression, crystallization and preliminary X-ray analysis of ligand-free human glutathione S-transferase M2-2.
  Acta Crystallogr D Biol Crystallogr, 54, 458-460.  
9817846 L.Prade, R.Huber, and B.Bieseler (1998).
Structures of herbicides in complex with their detoxifying enzyme glutathione S-transferase - explanations for the selectivity of the enzyme in plants.
  Structure, 6, 1445-1452.
PDB codes: 1bx9 1bye
9485454 M.Nicotra, M.Paci, M.Sette, A.J.Oakley, M.W.Parker, M.Lo Bello, A.M.Caccuri, G.Federici, and G.Ricci (1998).
Solution structure of glutathione bound to human glutathione transferase P1-1: comparison of NMR measurements with the crystal structure.
  Biochemistry, 37, 3020-3027.  
9012673 A.J.Oakley, J.Rossjohn, M.Lo Bello, A.M.Caccuri, G.Federici, and M.W.Parker (1997).
The three-dimensional structure of the human Pi class glutathione transferase P1-1 in complex with the inhibitor ethacrynic acid and its glutathione conjugate.
  Biochemistry, 36, 576-585.
PDB codes: 2gss 3gss
9037717 G.Chelvanayagam, M.C.Wilce, M.W.Parker, K.L.Tan, and P.G.Board (1997).
Homology model for the human GSTT2 Theta class glutathione transferase.
  Proteins, 27, 118-130.  
9261082 H.Savage, G.Montoya, C.Svensson, J.D.Schwenn, and I.Sinning (1997).
Crystal structure of phosphoadenylyl sulphate (PAPS) reductase: a new family of adenine nucleotide alpha hydrolases.
  Structure, 5, 895-906.
PDB code: 1sur
9287168 L.O.Hansson, M.Widersten, and B.Mannervik (1997).
Mechanism-based phage display selection of active-site mutants of human glutathione transferase A1-1 catalyzing SNAr reactions.
  Biochemistry, 36, 11252-11260.  
9351803 L.Prade, R.Huber, T.H.Manoharan, W.E.Fahl, and W.Reuter (1997).
Structures of class pi glutathione S-transferase from human placenta in complex with substrate, transition-state analogue and inhibitor.
  Structure, 5, 1287-1295.
PDB codes: 1aqv 1aqw 1aqx
9166793 M.Lo Bello, A.J.Oakley, A.Battistoni, A.P.Mazzetti, M.Nuccetelli, G.Mazzarese, J.Rossjohn, M.W.Parker, and G.Ricci (1997).
Multifunctional role of Tyr 108 in the catalytic mechanism of human glutathione transferase P1-1. Crystallographic and kinetic studies on the Y108F mutant enzyme.
  Biochemistry, 36, 6207-6217.
PDB code: 4gss
9188738 R.T.Koehler, H.O.Villar, K.E.Bauer, and D.L.Higgins (1997).
Ligand-based protein alignment and isozyme specificity of glutathione S-transferase inhibitors.
  Proteins, 28, 202-216.  
  9098897 W.M.Atkins, E.C.Dietze, and C.Ibarra (1997).
Pressure-dependent ionization of Tyr 9 in glutathione S-transferase A1-1: contribution of the C-terminal helix to a "soft" active site.
  Protein Sci, 6, 873-881.  
8810897 E.C.Dietze, C.Ibarra, M.J.Dabrowski, A.Bird, and W.M.Atkins (1996).
Rational modulation of the catalytic activity of A1-1 glutathione S-transferase: evidence for incorporation of an on-face (pi...HO-Ar) hydrogen bond at tyrosine-9.
  Biochemistry, 35, 11938-11944.  
8639625 E.C.Dietze, R.W.Wang, A.Y.Lu, and W.M.Atkins (1996).
Ligand effects on the fluorescence properties of tyrosine-9 in alpha 1-1 glutathione S-transferase.
  Biochemistry, 35, 6745-6753.  
8663072 G.Ricci, A.M.Caccuri, M.Lo Bello, N.Rosato, G.Mei, M.Nicotra, E.Chiessi, A.P.Mazzetti, and G.Federici (1996).
Structural flexibility modulates the activity of human glutathione transferase P1-1. Role of helix 2 flexibility in the catalytic mechanism.
  J Biol Chem, 271, 16187-16192.  
8672473 M.Widersten, R.Björnestedt, and B.Mannervik (1996).
Involvement of the carboxyl groups of glutathione in the catalytic mechanism of human glutathione transferase A1-1.
  Biochemistry, 35, 7731-7742.  
8917446 N.Sluis-Cremer, N.N.Naidoo, W.H.Kaplan, T.H.Manoharan, W.E.Fahl, and H.W.Dirr (1996).
Determination of a binding site for a non-substrate ligand in mammalian cytosolic glutathione S-transferases by means of fluorescence-resonance energy transfer.
  Eur J Biochem, 241, 484-488.  
8973647 N.Sluis-Cremer, N.Naidoo, and H.Dirr (1996).
Class-pi glutathione S-transferase is unable to regain its native conformation after oxidative inactivation by hydrogen peroxide.
  Eur J Biochem, 242, 301-307.  
8910329 T.E.McHugh, W.M.Atkins, J.K.Racha, K.L.Kunze, and D.L.Eaton (1996).
Binding of the aflatoxin-glutathione conjugate to mouse glutathione S-transferase A3-3 is saturated at only one ligand per dimer.
  J Biol Chem, 271, 27470-27474.  
8997900 T.Kunze (1996).
Phosphono analogues of glutathione as new inhibitors of glutathione S-transferases.
  Arch Pharm (Weinheim), 329, 503-509.  
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.