1f1w: Difference between revisions

Revision as of 13:33, 21 February 2008

SRC SH2 THREF1TRP MUTANT COMPLEXED WITH THE PHOSPHOPEPTIDE S(PTR)VNVQN

OverviewOverview

The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2 domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.

About this StructureAbout this Structure

1F1W is a Single protein structure of sequence from Gallus gallus. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

ReferenceReference

Structural basis for specificity switching of the Src SH2 domain., Kimber MS, Nachman J, Cunningham AM, Gish GD, Pawson T, Pai EF, Mol Cell. 2000 Jun;5(6):1043-9. PMID:10911998

Page seeded by OCA on Thu Feb 21 12:33:53 2008

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OCA

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-[[Image:1f1w.gif|left|200px]]<br /><applet load="1f1w" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:1f1w.gif|left|200px]]<br /><applet load="1f1w" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="1f1w, resolution 2.10&Aring;" />
 '''SRC SH2 THREF1TRP MUTANT COMPLEXED WITH THE PHOSPHOPEPTIDE S(PTR)VNVQN'''<br />
 ==Overview==
-The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended, conformation with a hydrophobic pocket, which includes ThrEF1, binding, Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an, Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2, domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV, phosphopeptides in a beta turn conformation, which, despite differing, conformations of the interacting tryptophan, closely resembles the native, Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution, therefore switches specificity by physically occluding the pTyr +3 binding, pocket and by providing additional interaction surface area for Asn(pY, +2). This demonstrates structurally how novel SH2 domain specificities may, rapidly evolve through single amino acid substitutions and suggests how, new signaling pathways may develop.
+The Src SH2 domain binds pYEEI-containing phosphopeptides in an extended conformation with a hydrophobic pocket, which includes ThrEF1, binding Ile(pY +3). Mutating ThrEF1 to tryptophan switches specificity to an Asn(pY +2) requirement, yielding a biological mimic of the Grb2 SH2 domain. Here we show that the Src ThrEF1Trp SH2 domain mutant binds pYVNV phosphopeptides in a beta turn conformation, which, despite differing conformations of the interacting tryptophan, closely resembles the native Grb2/pYVNV cognate peptide binding mode. The ThrEF1Trp substitution therefore switches specificity by physically occluding the pTyr +3 binding pocket and by providing additional interaction surface area for Asn(pY +2). This demonstrates structurally how novel SH2 domain specificities may rapidly evolve through single amino acid substitutions and suggests how new signaling pathways may develop.
 ==About this Structure==
-F1W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1F1W OCA].
+F1W is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1F1W OCA].
 ==Reference==
@@ Line 14: / Line 14: @@
 [[Category: Single protein]]
 [[Category: Transferase]]
-[[Category: Cunningham, A.M.]]
+[[Category: Cunningham, A M.]]
-[[Category: Gish, G.D.]]
+[[Category: Gish, G D.]]
-[[Category: Kimber, M.S.]]
+[[Category: Kimber, M S.]]
 [[Category: Nachman, J.]]
-[[Category: Pai, E.F.]]
+[[Category: Pai, E F.]]
 [[Category: Pawson, T.]]
 [[Category: phosphopeptide]]
@@ Line 25: / Line 25: @@
 [[Category: src]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Nov 20 14:31:50 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:33:53 2008''