1wt7: Difference between revisions

Revision as of 16:47, 21 February 2008

Solution structure of BuTX-MTX: a butantoxin-maurotoxin chimera

OverviewOverview

Scorpion toxins interact with their target ion channels through multiple molecular contacts. Because a "gain of function" approach has never been described to evaluate the importance of the molecular contacts in defining toxin affinity, we experimentally examined whether increasing the molecular contacts between a toxin and an ion channel directly impacts toxin affinity. For this purpose, we focused on two scorpion peptides, the well-characterized maurotoxin with its variant Pi1-like disulfide bridging (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as an N-terminal domain provider. BuTX is found to be 60-fold less potent than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues) further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in agreement with docking simulation data showing the importance of this domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain to MTX(Pi1) results in a chimera with five disulfide bridges (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to MTX(Pi1). Docking experiments performed with the 3-D structure of BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the N-terminal domain of BuTX participates in the increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicate that acting on molecular contacts between a toxin and a channel is an efficient strategy to modulate toxin affinity.

About this StructureAbout this Structure

1WT7 is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.

ReferenceReference

Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity., M'Barek S, Chagot B, Andreotti N, Visan V, Mansuelle P, Grissmer S, Marrakchi M, El Ayeb M, Sampieri F, Darbon H, Fajloun Z, De Waard M, Sabatier JM, Proteins. 2005 Aug 15;60(3):401-11. PMID:15971207

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-[[Image:1wt7.gif|left|200px]]<br /><applet load="1wt7" size="450" color="white" frame="true" align="right" spinBox="true"
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 caption="1wt7" />
 '''Solution structure of BuTX-MTX: a butantoxin-maurotoxin chimera'''<br />
 ==Overview==
-Scorpion toxins interact with their target ion channels through multiple, molecular contacts. Because a "gain of function" approach has never been, described to evaluate the importance of the molecular contacts in defining, toxin affinity, we experimentally examined whether increasing the, molecular contacts between a toxin and an ion channel directly impacts, toxin affinity. For this purpose, we focused on two scorpion peptides, the, well-characterized maurotoxin with its variant Pi1-like disulfide bridging, (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as, an N-terminal domain provider. BuTX is found to be 60-fold less potent, than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus, 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues), further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in, agreement with docking simulation data showing the importance of this, domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain, to MTX(Pi1) results in a chimera with five disulfide bridges, (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than, MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to, MTX(Pi1). Docking experiments performed with the 3-D structure of, BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the, N-terminal domain of BuTX participates in the increased affinity for Kv1.2, through additional molecular contacts. Altogether, the data indicate that, acting on molecular contacts between a toxin and a channel is an efficient, strategy to modulate toxin affinity.
+Scorpion toxins interact with their target ion channels through multiple molecular contacts. Because a "gain of function" approach has never been described to evaluate the importance of the molecular contacts in defining toxin affinity, we experimentally examined whether increasing the molecular contacts between a toxin and an ion channel directly impacts toxin affinity. For this purpose, we focused on two scorpion peptides, the well-characterized maurotoxin with its variant Pi1-like disulfide bridging (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as an N-terminal domain provider. BuTX is found to be 60-fold less potent than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues) further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in agreement with docking simulation data showing the importance of this domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain to MTX(Pi1) results in a chimera with five disulfide bridges (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to MTX(Pi1). Docking experiments performed with the 3-D structure of BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the N-terminal domain of BuTX participates in the increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicate that acting on molecular contacts between a toxin and a channel is an efficient strategy to modulate toxin affinity.
 ==About this Structure==
-WT7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1WT7 OCA].
+WT7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1WT7 OCA].
 ==Reference==
@@ Line 13: / Line 13: @@
 [[Category: Single protein]]
 [[Category: Andreotti, N.]]
-[[Category: Ayeb, M.El.]]
+[[Category: Ayeb, M El.]]
-[[Category: Barek, S.M.]]
+[[Category: Barek, S M.]]
 [[Category: Chagot, B.]]
 [[Category: Darbon, H.]]
@@ Line 21: / Line 21: @@
 [[Category: Mansuelle, P.]]
 [[Category: Marrakchi, M.]]
-[[Category: Sabatier, J.M.]]
+[[Category: Sabatier, J M.]]
 [[Category: Sampieri, F.]]
 [[Category: Visan, V.]]
-[[Category: Waard, M.De.]]
+[[Category: Waard, M De.]]
 [[Category: butantoxin]]
 [[Category: k+ channels]]
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 [[Category: toxin affinity]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 05:39:24 2007''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:47:51 2008''