Introduction:
RAS proteins play a key role of molecular switch in the
transduction of the growth signal from extracellular to intracellular
space. The state of the switch is "on" when GTP is bound and "off"
when GDP is bound to the protein. The "on" and "off" states
of the switch are distinguished by conformational differences that
span a length of more than 40 A, and are induced by the gamma-phosphate.
The most significant differences are localized in two regions: residues
30 to 38 (the switch I region) in the second loop and residues 60 to
76 (the switch II region) consisting of the fourth loop and the short alpha-helix
that follows the loop. Both regions are highly exposed and form a continuous
strip on the molecular surface most likely to be the recognition sites
for the effector and receptor molecule(or molecules).
RAS genes isolated from human tumors often have mutations
at positions corresponding to amino acid 12 or 61 of the encoded
protein (p21), while retroviral ras-encoded p21 contains substitutions
at both positions 12 and 59. These mutant proteins are deficient in
their GTP hydrolysis activity, and this loss of activity is linked
to their transforming potential.
Classification:
SCOP: cH-p21 Ras protein from Human (Homo sapiens)
Root:
scop
Class:
Alpha and beta proteins (a/b) Mainly parallel beta sheets (beta-alpha-beta
units)
Fold:
P-loop containing nucleotide triphosphate hydrolases 3 layers:
a/b/a, parallel or mixed beta-sheets of variable sizes
Superfamily: P-loop containing nucleotide
triphosphate hydrolases division into families based on beta-sheet
topologies
Family: G proteins
core: mixed beta-sheet of 6 strands, order 231456; strand 2 is
antiparallel to the rest
Protein: cH-p21
Ras protein
Species: Human (Homo
sapiens)
CATH
Homologous Superfamily 3.40.50.300 Alpha Beta 3-Layer(aba)
Sandwich Rossmann fold P-loop containing nucleotide triphosphate
hydrolases
Domain 4q2100
Structure:
The crystal structure at 2.7 A resolution of the normal
human c-H-ras oncogene protein lacking a flexible carboxyl-terminal
18 residue reveals that the protein consists of a six-stranded beta
sheet, four alpha helices, and nine connecting loops. Four loops
are involved in interactions with bound guanosine diphosphate: one
with the phosphates, another with the ribose, and two with the guanine
base. Most of the transforming proteins (in vivo and in vitro) have
single amino acid substitutions at one of a few key positions in three
of these four loops plus one additional loop. The biological functions
of the remaining five loops and other exposed regions are at present
unknown. However, one loop corresponds to the binding site for a neutralizing
monoclonal antibody and another to a putative "effector region"; mutations
in the latter region do not alter guanine nucleotide binding or guanosine
triphosphatase activity but they do reduce the transforming activity of
activated proteins.
Compound c-H-Ras p21 Protein Catalytic Domain
Complex With GDP
Molecular Weight
21282
Number of Residues 189
Number of Alpha 6
Content of Alpha 33.33
Number of Beta 6
Content of Beta
24.34
PROMOTIF
summary :
Experimental Details
Exp. Method: X-ray
Diffraction
Deposition Date: 25-Sep-1991
Released Date: 15-Jul-1992
Resolution [A]: 2.00
R-Value:
0.195
Space Group: I4
Unit Cell:
dim[A] a 96.30 b 96.30
c 41.37
angles
alpha 90 beta 90 gamma 90
HET groups:
ID
|
Name
|
Formula
|
PDB IDs
|
| GDP |
GUANOSINE-5'-DIPHOSPHATE |
C10H15N5O11P2 |
GDP |
| MG |
MAGNESIUM ION |
Mg |
MG |
Structure Neighbors for Chain
4Q21:_
(Size=171)
Criteria used: Z-Score>4.0 RMSD<3.0Å Gaps<10.0%
Sequence identity<50.0%
ID
NAME
2RAP:_
RAP2A
1G17:A
RAS-RELATED PROTEIN SEC4
1G17:B
RAS-RELATED PROTEIN SEC4
3RAB:A
RAB3A
3RAP:R
G PROTEIN RAP2A
3RAP:S
G PROTEIN RAP2A
1KAO:_
RAP2A
Structure Alignment - 4Q21:_
Sequence alignment based on assembled pairwise
structure alignments between 4Q21:_ and its neighbors. Light color
indicates not-aligned residues in structural neighbors. Position numbers
according to sequence (starting from 1) and according to PDB are given
as SSSS/PPPP, SSSS - sequence, PPPP - PDB.
4Q21:_ 1/2 MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTI-EDSYRKQVVIDGETCLLDILDTA
3RAB:A 3/21 DYMFKILIIGNSSVGKTSFLFRYADDSFTPAFVSTVGIDFKVKTIYRNDKRIKLQIWDTA
3RAP:R 2/3 -REYKVVVLGSGGVGKSALTVQFVTGTFIEKYDPTI-EDFYRKEIEVDSSPSVLEILDTA
1KAO:_ 1/2 MREYKVVVLGSGGVGKSALTVQFVTGTFIEKYDPTI-EDFYRKEIEVDSSPSVLEILDTA
4Q21:_ 60/61 GQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKR----VKDSDDVPMVLVG
3RAB:A 63/81 GQERYRTITTAYYRGAMGFILMYDITNEESFNAVQDWSTQIKTYSWDN-----AQVLLVG
3RAP:R 60/61 GTEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIR----VKRYEKVPVILVG
1KAO:_ 60/61 GTEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIR----VKRYEKVPVILVG
4Q21:_ 116/117 NKCDL-AARTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQH
3RAB:A 118/136 NKCDMEDERVVSSERGRQLADHLGFEFFEASAKDNINVKQTFERLVDVICEK
3RAP:R 116/117 NKVDLESEREVSSSEGRALAEEWGCPFMETSAKSKTMVDELFAEIVRQMNYA
1KAO:_ 116/117 NKVDLESEREVSSSEGRALAEEWGCPFMETSAKSKTMVDELFAEIVRQMNYA
| 3RAB:A
|
|
| 3RAP:R |
|
|
| 1KAO:_ |
|
|
|
|
4Q21:_ |
3RAB:A |
3RAP:R |
|
| Each cell in distance matrix provides: |
|
| RMSD(Å) |
Sequence identity(%) |
| Length of alignment |
Z-score |
|
|
CLUSTAL W multiple sequence
alignment
3RAP_R --MREYKVVVLGSGGVGKSALTVQFVTGTFIEKYDPTI-EDFYRKEIEVDSSPSVLEILD 57
1KAO__ --MREYKVVVLGSGGVGKSALTVQFVTGTFIEKYDPTI-EDFYRKEIEVDSSPSVLEILD 57
4Q21__ --MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTI-EDSYRKQVVIDGETCLLDILD 57
3RAB_A NFDYMFKILIIGNSSVGKTSFLFRYADDSFTPAFVSTVGIDFKVKTIYRNDKRIKLQIWD 60
:*::::* ..***::: .: . * : .*: * * : :.. *:* *
3RAP_R TAGTEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIRVKRYEKVPVILVGNK 117
1KAO__ TAGTEQFASMRDLYIKNGQGFILVYSLVNQQSFQDIKPMRDQIIRVKRYEKVPVILVGNK 117
4Q21__ TAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHQYREQIKRVKDSDDVPMVLVGNK 117
3RAB_A TAGQERYRTITTAYYRGAMGFILMYDITNEESFNAVQDWSTQIKTYS-WDNAQVLLVGNK 119
*** *.: :: * : . **: :: : * :**: :: ** . :.. ::*****
3RAP_R VDLESEREVSSSEGRALAEEWGCPFMETSAKSKTMVDELFAEIVRQMNYA---------- 167
1KAO__ VDLESEREVSSSEGRALAEEWGCPFMETSAKSKTMVDELFAEIVRQMNYA---------- 167
4Q21__ CDLAA-RTVESRQAQDLARSYGIPYIETSAKTRQGVEDAFYTLVREIRQHKLRKLNPPDE 176
3RAB_A CDMEDERVVSSERGRQLADHLGFEFFEASAKDNINVKQTFERLVDVICEK---------- 169
*: * *.* ..: ** * ::*:*** . *.: * :* :
3RAP_R -------------
1KAO__ -------------
4Q21__ SGPGCMSCKCVLS 189
3RAB_A -------------
References:
AUTHORS de Vos,A.M., Tong,L., Milburn,M.V., Matias,P.M.,
Jancarik,J., Noguchi,S., Nishimura,S., Miura,K., Ohtsuka,E.
and Kim,S.H.
TITLE Three-dimensional structure of an oncogene protein:
catalytic domain of human c-H-ras p21
JOURNAL Science 239 (4842), 888-893 (1988)
AUTHORS Prive,G.G., Milburn,M.V., Tong,L., de Vos,A.M.,
Yamaizumi,Z., Nishimura,S. and Kim,S.H.
TITLE X-ray crystal structures of transforming p21
ras mutants suggest a transition-state stabilization
mechanism for GTP hydrolysis
JOURNAL Proc. Natl. Acad. Sci. U.S.A. 89 (8), 3649-3653
(1992)
AUTHORS Brunger,A.T., Milburn,M.V., Tong,L., deVos,A.M.,
Jancarik,J., Yamaizumi,Z., Nishimura,S., Ohtsuka,E. and
Kim,S.H.
TITLE Crystal structure of an active form of RAS protein,
a complex of a GTP analog and the HRAS p21 catalytic
domain
JOURNAL Proc. Natl. Acad. Sci. U.S.A. 87 (12), 4849-4853
(1990)
