WORKLIST ENTRIES (1):
GSTRNSFRASEM View alignment View Structure Mu-class glutathione S-transferase signature
Type of fingerprint: COMPOUND with 4 elements
Links:
PRINTS; PR01266 GSTRNSFRASEA; PR01268 GSTRNSFRASEP; PR01269 SCRYSTALLIN
PRINTS; PR01625 GSTRNSFRASEO
PDB; 1GTU 3Dinfo
SCOP; 1GSB
CATH; 1GTU
Creation date 21-DEC-1999
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.BIOCHEM. 220 645-661 (1994).
4. TAKAHASHI, Y., CAMBELL, E.A., HIRATA, Y., TAKAYAMA, T. AND LISTOWSKY, I.
A basis for differentiating among the multiple human mu-glutathione
S-transferases and molecular cloning of brain GSTM5.
J.BIOL.CHEM. 268(12) 8893-8 (1993).
5. HANSSON, L.O., BOLTON-GROB, R., MASSOUD, T. AND MANNERVIK, B.
Evolution of differential substrate specificities in mu class glutathione
transferases probed by DNA shuffling.
J.MOL.BIOL. 287 265-276 (1999).
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 phenomenon 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].
At present, human mu-class GSTs can be subdivided into 5 isoforms based on
differing substrate specificities [4]. Mu-class GSTs are thought to be
involved in the detoxification of reactive oxygen species (cyclised
o-quinones) produced via oxidative metabolism of catecholamines. These
toxins are thought to be involved in neurological disorders of the
nigrostriatal and mesolimbic systems (Parkinsons and Schizophrenia,
respectively). Indeed, mu-class GSTs are expressed in the substantia nigra
and have preferential substrate specificity for the cyclised o-quinones
formed by catecholamine metabolism [5]. Mu-class GSTs possess the so-called
"mu-loop", which occurs between strand beta-2 and helix alpha-3. This is a
consequence of an insertion in the primary sequence and the loop allows the
overall domain I topology to remain [3].
GSTRNSFRASEM is a 4-element fingerprint that provides a signature for mu-
class glutathione S-transferases. The fingerprint was derived from an
initial alignment of 12 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length - motif 1 includes the
C-terminal region of beta-strand 2 and the loop between strand 2 and
alpha-helix 3; motif 2 spans helix 2 and the following loop; motif 3
includes the N-terminal region of helix 5; and motif 4 includes the
C-terminal region of helix 6 and the following loop. Three iterations on
SPTR37_10f were required to reach convergence, at which point a true set
comprising 22 sequences was identified. Three partial matches were also
found: GTM1_DERPT and O16058 are mu-class glutathione transferases from
Dermatophagoides pteronyssinus (house-dust mite) and Echinococcus
granulosus, respectively, which match motifs 1 and 2; and Q27653 is
an unclassified GST that again matches motifs 1 and 2.
SUMMARY INFORMATION
22 codes involving 4 elements
0 codes involving 3 elements
3 codes involving 2 elements
COMPOSITE FINGERPRINT INDEX
4| 22 22 22 22
3| 0 0 0 0
2| 3 3 0 0
--+---------------------
| 1 2 3 4
True positives..
GTM5_HUMAN GTM3_RAT GTM1_HUMAN GTMU_CRILO
GTM4_HUMAN Q05465 GTM2_MOUSE GTM1_RAT
GTM2_RAT GTM1_MOUSE GTM3_MOUSE O35660
GTMU_MESAU GTMU_CAVPO O60550 GTM2_HUMAN
GTM3_HUMAN GTMU_RABIT Q9Z1B2 GTM5_MOUSE
GTM2_CHICK O97117
Subfamily: Codes involving 2 elements
Subfamily True positives..
GTM1_DERPT Q27653 O16058
PROTEIN TITLES
GTM5_HUMAN GLUTATHIONE S-TRANSFERASE MU 5 (EC 2.5.1.18) (GSTM5-5) (GST
GTM3_RAT GLUTATHIONE S-TRANSFERASE YB3 (EC 2.5.1.18) (CHAIN 4) (GST C
GTM1_HUMAN GLUTATHIONE S-TRANSFERASE MU 1 (EC 2.5.1.18) (GSTM1-1) (HB S
GTMU_CRILO GLUTATHIONE S-TRANSFERASE Y1 (EC 2.5.1.18) (CHAIN 3) (GST CL
GTM4_HUMAN GLUTATHIONE S-TRANSFERASE MU 4 (EC 2.5.1.18) (GSTM4-4) (GTS-
Q05465 GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (CLASS-MU) - HOMO SA
GTM2_MOUSE GLUTATHIONE S-TRANSFERASE 5 (EC 2.5.1.18) (GST 5-5) (GST CLA
GTM1_RAT GLUTATHIONE S-TRANSFERASE YB1 (EC 2.5.1.18) (CHAIN 3) (GST M
GTM2_RAT GLUTATHIONE S-TRANSFERASE YB2 (EC 2.5.1.18) (CHAIN 4) (GST C
GTM1_MOUSE GLUTATHIONE S-TRANSFERASE GT8.7 (EC 2.5.1.18) (GST 1-1) (GST
GTM3_MOUSE GLUTATHIONE S-TRANSFERASE GT9.3 (EC 2.5.1.18) (GST CLASS-MU)
O35660 GLUTATHIONE-S-TRANSFERASE CLASS M5 (EC 2.5.1.18) (GLUTATHION
GTMU_MESAU GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (GST CLASS-MU) - MES
GTMU_CAVPO GLUTATHIONE S-TRANSFERASE B (EC 2.5.1.18) (GST B) (GST CLASS
O60550 GLUTATHIONE S-TRANSFERASE MU 3 - HOMO SAPIENS (HUMAN).
GTM2_HUMAN GLUTATHIONE S-TRANSFERASE MU 2 (EC 2.5.1.18) (GSTM2-2) (GST
GTM3_HUMAN GLUTATHIONE S-TRANSFERASE MU 3 (EC 2.5.1.18) (GSTM3-3) (GST
GTMU_RABIT GLUTATHIONE S-TRANSFERASE MU 1 (EC 2.5.1.18) (GST MU I) (GST
Q9Z1B2 GLUTATHIONE S-TRANSFERASE M5 (EC 2.5.1.18) - RATTUS NORVEGIC
GTM5_MOUSE GLUTATHIONE S-TRANSFERASE MU 5 (EC 2.5.1.18) (GSTM5-5) (GST
GTM2_CHICK GLUTATHIONE S-TRANSFERASE 2 (EC 2.5.1.18) (GST-CL2) (GST CLA
O97117 GLUTATHIONE S-TRANSFERASE - BOOPHILUS MICROPLUS (CATTLE TICK
GTM1_DERPT GLUTATHIONE S-TRANSFERASE (EC 2.5.1.18) (GST CLASS-MU) (MAJO
Q27653 GLUTATHIONE TRANSFERASE (EC 2.5.1.18) (GLUTATHIONE S-ALKYLTR
O16058 GLUTATHIONE S-TRANSFERASE - ECHINOCOCCUS GRANULOSUS.
SCAN HISTORY
SPTR37_10f 3 90 NSINGLE
INITIAL MOTIF SETS
GSTRNSFRASEM1 Length of motif = 13 Motif number = 1
Mu-class glutathione S-transferase motif I - 1
PCODE ST INT
KKYTMGDAPDYDR GTM1_HUMAN 30 30
KRYAMGDAPDYDR GTM1_RAT 30 30
KRYTMGDAPDFDR GTM1_MOUSE 30 30
KKYTMGDAPDYDR GTM2_HUMAN 30 30
KKYSMGDAPDYDR GTM2_RAT 30 30
KKYTMGDAPDYDR GTM2_MOUSE 30 30
KRYTCGEAPDYDR GTM3_HUMAN 35 35
KRYTMGDAPDFDR GTM3_RAT 30 30
KRYVMGDAPNFDR GTM3_MOUSE 30 30
KKYTMGDAPDYDR GTM4_HUMAN 31 31
KKYTMGDAPDYDR GTM5_HUMAN 30 30
KRYICGEAPDYDR GTM5_MOUSE 34 34
GSTRNSFRASEM2 Length of motif = 13 Motif number = 2
Mu-class glutathione S-transferase motif II - 1
PCODE ST INT
SQWLNEKFKLGLD GTM1_HUMAN 43 0
SQWLNEKFKLGLD GTM1_RAT 43 0
SQWLNEKFKLGLD GTM1_MOUSE 43 0
SQWLNEKFKLGLD GTM2_HUMAN 43 0
SQWLSEKFKLGLD GTM2_RAT 43 0
SQWLSEKFKLGLD GTM2_MOUSE 43 0
SQWLDVKFKLDLD GTM3_HUMAN 48 0
SQWLNEKFKLGLD GTM3_RAT 43 0
SQWLSEKFNLGLD GTM3_MOUSE 43 0
SQWLNEKFKLGLD GTM4_HUMAN 44 0
SQWLNEKFKLGLD GTM5_HUMAN 43 0
SQWLDVKFKLDLD GTM5_MOUSE 47 0
GSTRNSFRASEM3 Length of motif = 12 Motif number = 3
Mu-class glutathione S-transferase motif III - 1
PCODE ST INT
CGETEEEKIRVD GTM1_HUMAN 86 30
CGETEEERIRAD GTM1_RAT 86 30
DGETEEERIRAD GTM1_MOUSE 86 30
CGESEKEQIRED GTM2_HUMAN 86 30
CGETEEERIRVD GTM2_RAT 86 30
CGETEEERIRVD GTM2_MOUSE 86 30
CGETEEEKIRVD GTM3_HUMAN 91 30
CGETEEERIRVD GTM3_RAT 86 30
CGETEEERIRVD GTM3_MOUSE 86 30
CGETEEEKIRVD GTM4_HUMAN 87 30
CGETEEEKIRVD GTM5_HUMAN 86 30
CGDTEEEKIRVD GTM5_MOUSE 90 30
GSTRNSFRASEM4 Length of motif = 14 Motif number = 4
Mu-class glutathione S-transferase motif IV - 1
PCODE ST INT
SEFLGKRPWFAGNK GTM1_HUMAN 138 40
SEFLGKRPWFAGDK GTM1_RAT 138 40
SEFLGKRPWFAGDK GTM1_MOUSE 138 40
SQFLGKQPWFLGDK GTM2_HUMAN 138 40
SEFLGKQPWFAGNK GTM2_RAT 138 40
SEFLGKQPWFAGNK GTM2_MOUSE 138 40
SMFLWKFSWFAGEK GTM3_HUMAN 143 40
SEFLGKRPWFAGDK GTM3_RAT 138 40
SEFLGKRPWFAGDK GTM3_MOUSE 138 40
SQFLGKRPWFVGDK GTM4_HUMAN 139 40
SEFLGKRPWFAGDK GTM5_HUMAN 138 40
SLFLGKFTWFAGEK GTM5_MOUSE 142 40
FINAL MOTIF SETS
GSTRNSFRASEM1 Length of motif = 13 Motif number = 1
Mu-class glutathione S-transferase motif I - 3
PCODE ST INT
KKYTMGDAPDYDR GTM5_HUMAN 30 30
KRYTMGDAPDFDR GTM3_RAT 30 30
KKYTMGDAPDYDR GTM1_HUMAN 30 30
KKYTMGDAPDSDR GTMU_CRILO 30 30
KKYTMGDAPDYDR GTM4_HUMAN 31 31
KKYTMGDAPDYDR Q05465 31 31
KKYTMGDAPDYDR GTM2_MOUSE 30 30
KRYAMGDAPDYDR GTM1_RAT 30 30
KKYSMGDAPDYDR GTM2_RAT 30 30
KRYTMGDAPDFDR GTM1_MOUSE 30 30
KRYVMGDAPNFDR GTM3_MOUSE 30 30
RRYAMGDAPDYDR O35660 31 31
KKYTMGDAPNFDR GTMU_MESAU 30 30
KRYNMGDAPDYDR GTMU_CAVPO 30 30
KRYTCGEAPDYDR O60550 35 35
KKYTMGDAPDYDR GTM2_HUMAN 30 30
KRYTCGEAPDYDR GTM3_HUMAN 35 35
KKYTMGDAPNYDQ GTMU_RABIT 30 30
KQYTCGEAPDYDR Q9Z1B2 35 35
KRYICGEAPDYDR GTM5_MOUSE 34 34
RRYKAGPAPDFDP GTM2_CHICK 30 30
KRYTCGPPPDFDR O97117 31 31
GSTRNSFRASEM2 Length of motif = 13 Motif number = 2
Mu-class glutathione S-transferase motif II - 3
PCODE ST INT
SQWLNEKFKLGLD GTM5_HUMAN 43 0
SQWLNEKFKLGLD GTM3_RAT 43 0
SQWLNEKFKLGLD GTM1_HUMAN 43 0
SQWLNEKFKLGLD GTMU_CRILO 43 0
SQWLNEKFKLGLD GTM4_HUMAN 44 0
SQWLNEKFKLGLD Q05465 44 0
SQWLSEKFKLGLD GTM2_MOUSE 43 0
SQWLNEKFKLGLD GTM1_RAT 43 0
SQWLSEKFKLGLD GTM2_RAT 43 0
SQWLNEKFKLGLD GTM1_MOUSE 43 0
SQWLSEKFNLGLD GTM3_MOUSE 43 0
SQWLNDKFKLXLD O35660 44 0
SQWLNEKFKLGLD GTMU_MESAU 43 0
SQWLNEKFKLGLD GTMU_CAVPO 43 0
SQWLDVKFKLDLD O60550 48 0
SQWLNEKFKLGLD GTM2_HUMAN 43 0
SQWLDVKFKLDLD GTM3_HUMAN 48 0
SKWLSEKFTLGLD GTMU_RABIT 43 0
SQWLDVKFKLDLD Q9Z1B2 48 0
SQWLDVKFKLDLD GTM5_MOUSE 47 0
SDWTNEKEKLGLD GTM2_CHICK 43 0
SSWLNEKTKLGLE O97117 44 0
GSTRNSFRASEM3 Length of motif = 12 Motif number = 3
Mu-class glutathione S-transferase motif III - 3
PCODE ST INT
CGETEEEKIRVD GTM5_HUMAN 86 30
CGETEEERIRVD GTM3_RAT 86 30
CGETEEEKIRVD GTM1_HUMAN 86 30
CGETEEERIRVD GTMU_CRILO 86 30
CGETEEEKIRVD GTM4_HUMAN 87 30
CGETEEEKIRVD Q05465 87 30
CGETEEERIRVD GTM2_MOUSE 86 30
CGETEEERIRAD GTM1_RAT 86 30
CGETEEERIRVD GTM2_RAT 86 30
DGETEEERIRAD GTM1_MOUSE 86 30
CGETEEERIRVD GTM3_MOUSE 86 30
CGETEEERIRVD O35660 87 30
CGETEEERIQLD GTMU_MESAU 86 30
CGVTEEETIRMD GTMU_CAVPO 86 30
CGETEEEKIRVD O60550 91 30
CGESEKEQIRED GTM2_HUMAN 86 30
CGETEEEKIRVD GTM3_HUMAN 91 30
CGETEEERIRVD GTMU_RABIT 86 30
CGDTEEEKIRVD Q9Z1B2 91 30
CGDTEEEKIRVD GTM5_MOUSE 90 30
CGETEVEKQRVD GTM2_CHICK 86 30
EGKTEAEKQRVD O97117 87 30
GSTRNSFRASEM4 Length of motif = 14 Motif number = 4
Mu-class glutathione S-transferase motif IV - 3
PCODE ST INT
SEFLGKRPWFAGDK GTM5_HUMAN 138 40
SEFLGKRPWFAGDK GTM3_RAT 138 40
SEFLGKRPWFAGNK GTM1_HUMAN 138 40
SEFLGKRPWFAGDK GTMU_CRILO 138 40
SQFLGKRPWFVGDK GTM4_HUMAN 139 40
SQFLGKRPWFVGDK Q05465 139 40
SEFLGKQPWFAGNK GTM2_MOUSE 138 40
SEFLGKRPWFAGDK GTM1_RAT 138 40
SEFLGKQPWFAGNK GTM2_RAT 138 40
SEFLGKRPWFAGDK GTM1_MOUSE 138 40
SEFLGKRPWFAGDK GTM3_MOUSE 138 40
SEFLGKQPWFAGDK O35660 139 40
SEFLGKRSWFAGDK GTMU_MESAU 138 40
SQFLGKLPWFAGNK GTMU_CAVPO 138 40
SMFLGKFSWFAGEK O60550 143 40
SQFLGKQPWFLGDK GTM2_HUMAN 138 40
SMFLWKFSWFAGEK GTM3_HUMAN 143 40
SQFLGSLPWFAGDK GTMU_RABIT 138 40
SLFLGKFTWFAGEK Q9Z1B2 143 40
SLFLGKFTWFAGEK GTM5_MOUSE 142 40
SRFLGSRSWFVGDK GTM2_CHICK 138 40
SDYLGTHKFFAGDN O97117 139 40
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