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2kni

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Revision as of 09:41, 26 February 2020

High-resolution solution structure of the ASIC1a blocker PcTX1

Structural highlights

2kni is a 1 chain structure with sequence from Psaca. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	1lmm
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TXP1_PSACA] Potently and selectively blocks the acid-sensing ion channel ASIC1a/ACCN2. The blockade is rapid and reversible. Psalmotoxin 1 loses its capacity to block ASIC1a/ACCN2 as soon as this subunit is associated with another member of the family (ASIC2a/ACCN1 or ASIC3/ACCN3). The toxin can distinguish between the two ASIC1/ACCN2 splice variants ASIC1a/ACCN2 and ASIC1b/ACCN2.^[1]

Publication Abstract from PubMed

Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is pi-TRTX-Pc1a (PcTx1), a disulfide-rich 40-residue peptide isolated from spider venom. pi-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the pi-TRTX-Pc1a-ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of pi-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a beta-hairpin loop that was revealed to be mobile over a wide range of time scales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin-receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side-chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of pi-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful pi-TRTX-Pc1a mimetics.

A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a.,Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug, 8. PMID:21825095^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Escoubas P, De Weille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Menez A, Lazdunski M. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem. 2000 Aug 18;275(33):25116-21. PMID:10829030 doi:http://dx.doi.org/10.1074/jbc.M003643200
↑ Saez NJ, Mobli M, Bieri M, Chassagnon IR, Malde AK, Gamsjaeger R, Mark AE, Gooley PR, Rash LD, King GF. A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. Mol Pharmacol. 2011 Nov;80(5):796-808. doi: 10.1124/mol.111.072207. Epub 2011 Aug, 8. PMID:21825095 doi:http://dx.doi.org/10.1124/mol.111.072207

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2kni"

@@ Line 1: / Line 1: @@
 ==High-resolution solution structure of the ASIC1a blocker PcTX1==
-<StructureSection load='2kni' size='340' side='right' caption='[[2kni]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''>
+<StructureSection load='2kni' size='340' side='right'caption='[[2kni]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2kni]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Psaca Psaca]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KNI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KNI FirstGlance]. <br>
@@ Line 22: / Line 22: @@
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Psaca]]
 [[Category: King, G F]]

2kni

From Proteopedia

Revision as of 09:41, 26 February 2020

High-resolution solution structure of the ASIC1a blocker PcTX1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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