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PR01268

Identifier
GSTRNSFRASEP  [View Relations]  [View Alignment]  
Accession
PR01268
No. of Motifs
3
Creation Date
21-DEC-1999
Title
Pi-class glutathione S-transferase signature
Database References

PDB; 1GSS
SCOP; 1GSS
CATH; 1GSS
Literature References
1. ALLARDYCE, C.S., MCDONAGH, P.D., LIAN, L-Y., WOLF, R. AND ROBERTS, G.C.K.
The role of tyrosine-9 and the C-terminal helix in the catalytic mechanism
of Alpha-class glutathione S-transferases.
BIOCHEM.J. 343 525-531 (1999).
 
2. NUCCETELLI, M.N., MAZZETTI, A.P., ROSSJOHN, J., PARKER, M.W., BOARD, P.,
CACCURI, A.M., FEDERICI, G., RICCI, G. AND LO BELLO, M.
Shifting substrate specificity of human glutathione transferase (from class
Pi to class Alpha) by a single point mutation.
BIOCHEM.BIOPHYS.RES.COMMUN. 252(1) 184-189 (1998).
 
3. DIRR, H., REINEMER, P. AND HUBER, R.
X-Ray crystal structures of cytosolic glutathione S-transferases.
Implications for protein architecture, substrate recognition and catalytic
function.
EUR.J.BIOCHEMISTRY 220 645-661 (1994).
 
4. HENDERSON, C.J., SMITH, A.G., URE, J., BROWN, K., BACON, E.J. 
AND WOLF, C.R.
Increased skin tumourigenesis in mice lacking pi-class glutathione
S-transferases.
PROC.NATL.ACAD.SCI.U.S.A. 95 5275-5280 (1998).

Documentation
Glutathione S-transferases (GSTs) are a range of dimeric proteins that
catalyse the conjugation of glutathione to a wide range of hydrophobic
compounds through the formation of a thioether bond with their
electrophilic centre. Based on amino acid sequence identity, there are at
least seven major classes of GST (designated alpha, kappa, mu, pi, sigma, 
theta and zeta). Pi-, mu-, alpha- and theta-class crystal structures have
been elucidated; all possess a similar GSH-binding site (G subsite), but
the hydrophobic substrate-binding site (H subsite) is subject to variation 
across the classes [1]. Whilst most of the GSTs share common substrates,
there are distinct differences in substrate preference between subfamilies.
Sequence similarity between classes is rather low, ranging between 20-30%.
However, a single point mutation in the H-subsite region is enough to shift
substrate specificity from class pi to alpha [2].
 
These enzymes have evolved as a cellular protection system against a range
of xenobiotics, oxidative metabolism by-products, and in particular are
known to metabolise a number of environmental carcinogens. The wide range
of GST isoforms present in the various subfamilies provides cells with an
efficient way of scavenging the huge number of potentially toxic compounds
encountered. Genetic differences in GST expression have been implicated in
individual susceptibility to certain types of cancer. Conversely, over- 
expression of GSTs is thought to be involved in the phenomenom of multi-drug
resistance to cancer chemotherapy.
 
In spite of relatively low sequence identity, the GSTs exhibit a high degree
of structural similarity. The structure comprises 2 domains: domain I is the
smaller of the two and is formed from the N-terminal region of the sequence
- it possesses an alpha/beta-type core structure comprising a central 
4-stranded beta-pleated sheet, flanked on one side by two alpha-helices and
on the other by a single helix; domain II is the larger of the domains and
occurs towards the C-terminal region of the sequence - it contains a
predominantly all-alpha-type core comprising 5 amphipathic alpha-helices,
arranged in a right-handed spiral. The active site is situated near the
subunit interface. G-subsite molecular recognition is attributable mostly 
to residues in domain I of one subunit and 1 or 2 residues in domain II of
the other subunit. Residues contributing to H-subsite specificity are found
within domains I and II of the same subunit [3].
 
Pi-class GSTs are recognised by ethacrynic acid substrate specificity [2].
The pi-class H subsite has been found to be comparatively open [1], perhaps
explaining specificity towards the lesser hydrophobic substrates. This class
has received particular interest in relation to carcinogenesis. Pi-class 
GSTs have been found to be markedly increased in the early stages of rat
liver carcinogenesis. Expression levels of GST-P have also been found to be
elevated in many human tumours. In addition, polycyclic aromatic hydrocarbon
(a carcinogen found in cigarette smoke) induced tumourigenesis is increased
in mice lacking this enzyme [4].
 
GSTRNSFRASEP is a 3-element fingerprint that provides a signature for pi-
class glutathione S-transferases. The fingerprint was derived from an
initial alignment of 5 sequences: the motifs were drawn from conserved
regions spanning the full alignment length - motif 1 spans beta-strands
3 and 4, which run anti-parallel via a beta hairpin; motif 2 includes the 
C-terminal portion of helix 4 and helices 5 and 6; and motif 3 spans the
C-terminal region of helix 11, helix 12 and the following loop. Two 
iterations on SPTR37_10f were required to reach convergence, at which point
a true set comprising 19 sequences was identified. 
Summary Information
19 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3191919
2000
123
True Positives
GTP1_MOUSE    GTP2_MOUSE    GTP_BOVIN     GTP_CAEEL     
GTP_CRILO GTP_CRIMI GTP_DIRIM GTP_HUMAN
GTP_MACMU GTP_MESAU GTP_ONCVO GTP_PIG
GTP_RAT O00460 O02636 O61750
P91505 Q15690 Q27711
Sequence Titles
GTP1_MOUSE  GLUTATHIONE S-TRANSFERASE P 1 (EC 2.5.1.18) (GST YF-YF) (GST-PIB) (GST CLASS-PI) 
GTP2_MOUSE GLUTATHIONE S-TRANSFERASE P 2 (EC 2.5.1.18) (GST YF-YF) (GST-PIA) (GST CLASS-PI)
GTP_BOVIN GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - BOS TAURUS (BOVINE).
GTP_CAEEL GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - CAENORHABDITIS ELEGAN
GTP_CRILO GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - CRICETULUS LONGICAUDA
GTP_CRIMI GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - CRICETULUS MIGRATORIU
GTP_DIRIM GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (GST CLASS-PI) - DIROFILARIA IMMITIS.
GTP_HUMAN GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) (GSTP1-1) - HOMO SAPIEN
GTP_MACMU GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - MACACA MULATTA (RHESU
GTP_MESAU GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST CLASS-PI) - MESOCRICETUS AURATUS
GTP_ONCVO GLUTATHIONE S-TRANSFERASE 2 (EC 2.5.1.18) (GST CLASS-PI) - ONCHOCERCA VOLVULUS.
GTP_PIG GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST P1-1) (GST CLASS-PI) - SUS SCROFA
GTP_RAT GLUTATHIONE S-TRANSFERASE P (EC 2.5.1.18) (GST 7-7) (CHAIN 7) (GST CLASS-PI) - R
O00460 GLUTATHIONE S-TRANSFERASE - HOMO SAPIENS (HUMAN).
O02636 GLUTATHIONE TRANSFERASE (EC 2.5.1.18) (GLUTATHIONE S-ALKYLTRANSFERASE) (GLUTATHI
O61750 F37F2.3 PROTEIN - CAENORHABDITIS ELEGANS.
P91505 SIMILAR TO GLUTATHIONE S-TRANSFERASE - CAENORHABDITIS ELEGANS.
Q15690 GLUTATHIONE S-TRANSFERASE-P1C - HOMO SAPIENS (HUMAN).
Q27711 GLUTATHIONE TRANSFERASE (EC 2.5.1.18) (GLUTATHIONE S-ALKYLTRANSFERASE) (GLUTATHI
Scan History
SPTR37_10f 2  300  NSINGLE    
Initial Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
CLYGQLPKFEDGDLTLY GTP_RAT 47 47 -
CLYGQLPKFQDGDLTLY GTP_HUMAN 47 47 -
FQFGQLPCLYDGDQQIV GTP_ONCVO 45 45 -
MIFGQVPCLLSGDEEIV GTP_CAEEL 45 45 -
FQFGQLPCFYDGDQQIV GTP_DIRIM 45 45 -

Motif 2 width=22
Element Seqn Id St Int Rpt
LRCKYGTLIYTNYENGKDDYVK GTP_RAT 99 35 -
LRCKYISLIYTNYEAGKDDYVK GTP_HUMAN 99 35 -
LHVKYTRMIYMAYETEKDPYIK GTP_ONCVO 97 35 -
LHTKYTTMIYRNYEDGKAPYIK GTP_CAEEL 97 35 -
LHSKYTRMIYEAYETQKDPFIK GTP_DIRIM 97 35 -

Motif 3 width=20
Element Seqn Id St Int Rpt
KAFLSSPDHLNRPINGNGKQ GTP_RAT 190 69 -
KAFLASPEYVNLPINGNGKQ GTP_HUMAN 190 69 -
KEYCEKRDAAKVPVNGNGKQ GTP_ONCVO 189 70 -
KAYLNKRAAINPPVNGNGKQ GTP_CAEEL 189 70 -
KEYCAKRNASKMPVNGNGKQ GTP_DIRIM 189 70 -
Final Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
CLYGQLPKFEDGDLTLY GTP_CRIMI 47 47 -
CLYGQLPKFQDGDLTLY GTP_MACMU 47 47 -
CLYGQLPKFQDGDLTLY O00460 48 48 -
CLYGQLPKFEDGDLTLY GTP_RAT 47 47 -
CLYGQLPKFEDGDLTLY GTP_CRILO 47 47 -
CLYGQLPKFQDGDLTLY GTP_HUMAN 47 47 -
CLYGQLPKFQDGDLTLY Q15690 48 48 -
CLYGQLPKFEDGDLTLY GTP1_MOUSE 47 47 -
CLYGQLPKFQDGDLTLY GTP_BOVIN 47 47 -
CLYGQLPKFEDGDLILY GTP_MESAU 47 47 -
CLYGQLPKFEDGDLTLY GTP2_MOUSE 47 47 -
CLFRQLPKFQDGDLTLY GTP_PIG 45 45 -
FQFGQLPCLYDGDQQIV GTP_ONCVO 45 45 -
FQFGQLPCLYDGDQQIV Q27711 45 45 -
MIFGQVPCLLSGDEEIV GTP_CAEEL 45 45 -
FQFGQLPCFYDGDQQIV GTP_DIRIM 45 45 -
FHFGQLPCLYDGDHQIV O02636 45 45 -
MIFAQLPCLHIGTETIV P91505 45 45 -
MIFGSCPCLTMGDKEIV O61750 45 45 -

Motif 2 width=22
Element Seqn Id St Int Rpt
LRCKYVTLIYTKYEEGKDDYVK GTP_CRIMI 99 35 -
LRCKYLSLIYTNYEAGKDDYVK GTP_MACMU 99 35 -
LRCKYVSLIYTNYEAGKDDYVK O00460 100 35 -
LRCKYGTLIYTNYENGKDDYVK GTP_RAT 99 35 -
LRCKYITLIYTKYEEGKDDYVK GTP_CRILO 99 35 -
LRCKYISLIYTNYEAGKDDYVK GTP_HUMAN 99 35 -
LRCKYVSLIYTNYEVGKDDYVK Q15690 100 35 -
LRGKYVTLIYTNYENGKNDYVK GTP1_MOUSE 99 35 -
LRCKYVSLIYTNYEAGKEDYVK GTP_BOVIN 99 35 -
LRCKYVTLIYTKYEEGKDDYVK GTP_MESAU 99 35 -
LRGKYGTMIYRNYENGKNDYVK GTP2_MOUSE 99 35 -
LRCKYATLIYTNYEAGKEKYVK GTP_PIG 97 35 -
LHVKYTRMIYMAYETEKDPYIK GTP_ONCVO 97 35 -
LHVKYTRMIYMAYETEKDPYIK Q27711 97 35 -
LHTKYTTMIYRNYEDGKAPYIK GTP_CAEEL 97 35 -
LHSKYTRMIYEAYETQKDPFIK GTP_DIRIM 97 35 -
LHTKYTKMIYQAYDTEKDSYIK O02636 97 35 -
LRTKYFTMIKTDYEDGKEAYIT P91505 97 35 -
LHATYATMIYQNYENGRQPFIQ O61750 97 35 -

Motif 3 width=20
Element Seqn Id St Int Rpt
KAFLSSPDHVNRPINGNGKQ GTP_CRIMI 190 69 -
KAFLASPEHVNLPINGNGKQ GTP_MACMU 190 69 -
KAFLASPEYVNLPINGNGKQ O00460 191 69 -
KAFLSSPDHLNRPINGNGKQ GTP_RAT 190 69 -
KAFLSSPDHVNRPINGNGKQ GTP_CRILO 190 69 -
KAFLASPEYVNLPINGNGKQ GTP_HUMAN 190 69 -
KAFLASPEYVNLPINGNGKQ Q15690 191 69 -
KAFLSSPEHVNRPINGNGKQ GTP1_MOUSE 190 69 -
KAFLASPEHMNRPINGNGKQ GTP_BOVIN 190 69 -
KAFLSSPDHVNRPINGNGKQ GTP_MESAU 190 69 -
KAFLSSPEHVNRPINGNGKQ GTP2_MOUSE 190 69 -
KAFLASPEHVNRPINGNGKN GTP_PIG 188 69 -
KEYCEKRDAAKVPVNGNGKQ GTP_ONCVO 189 70 -
KEYCEKRDAAKVPVNGNGKQ Q27711 189 70 -
KAYLNKRAAINPPVNGNGKQ GTP_CAEEL 189 70 -
KEYCAKRNASKMPVNGNGKQ GTP_DIRIM 189 70 -
KEYCKQRNRAKIPVNGNGKQ O02636 189 70 -
RLYLNKRAELNPFVSGNGKQ P91505 189 70 -
TEYLKKRAIMKTPVNGNGKQ O61750 189 70 -