Ivermectin binding sites in human and invertebrate Cys-loop receptors

Timothy Peter Lynagh; Joseph W Lynch

doi:10.1016/j.tips.2012.05.002

Ivermectin binding sites in human and invertebrate Cys-loop receptors

Timothy Peter Lynagh, Joseph W Lynch

57 Citationer (Scopus)

Abstract

Ivermectin is a gold standard antiparasitic drug that has been used successfully to treat billions of humans, livestock and pets. Until recently, the binding site on its Cys-loop receptor target had been a mystery. Recent protein crystal structures, site-directed mutagenesis data and molecular modelling now explain how ivermectin binds to these receptors and reveal why it is selective for invertebrate members of the Cys-loop receptor family. Combining this with emerging genomic information, we are now in a position to predict species sensitivity to ivermectin and better understand the molecular basis of ivermectin resistance. An understanding of the molecular structure of the ivermectin binding site, which is formed at the interface of two adjacent subunits in the transmembrane domain of the receptor, should also aid the development of new lead compounds both as anthelmintics and as therapies for a wide variety of human neurological disorders.

Originalsprog	Engelsk
Tidsskrift	Trends in Pharmacological Sciences
Vol/bind	33
Udgave nummer	8
Sider (fra-til)	432-41
Antal sider	10
ISSN	0165-6147
DOI	https://doi.org/10.1016/j.tips.2012.05.002
Status	Udgivet - aug. 2012

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10.1016/j.tips.2012.05.002

Citationsformater

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title = "Ivermectin binding sites in human and invertebrate Cys-loop receptors",

abstract = "Ivermectin is a gold standard antiparasitic drug that has been used successfully to treat billions of humans, livestock and pets. Until recently, the binding site on its Cys-loop receptor target had been a mystery. Recent protein crystal structures, site-directed mutagenesis data and molecular modelling now explain how ivermectin binds to these receptors and reveal why it is selective for invertebrate members of the Cys-loop receptor family. Combining this with emerging genomic information, we are now in a position to predict species sensitivity to ivermectin and better understand the molecular basis of ivermectin resistance. An understanding of the molecular structure of the ivermectin binding site, which is formed at the interface of two adjacent subunits in the transmembrane domain of the receptor, should also aid the development of new lead compounds both as anthelmintics and as therapies for a wide variety of human neurological disorders.",

keywords = "Amino Acid Sequence, Animals, Antiparasitic Agents, Binding Sites, Crystallography, X-Ray, Cysteine Loop Ligand-Gated Ion Channel Receptors, Humans, Invertebrates, Ivermectin, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Conformation",

author = "Lynagh, {Timothy Peter} and Lynch, {Joseph W}",

year = "2012",

month = aug,

doi = "10.1016/j.tips.2012.05.002",

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volume = "33",

pages = "432--41",

journal = "Trends in Pharmacological Sciences",

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T1 - Ivermectin binding sites in human and invertebrate Cys-loop receptors

AU - Lynagh, Timothy Peter

AU - Lynch, Joseph W

PY - 2012/8

Y1 - 2012/8

N2 - Ivermectin is a gold standard antiparasitic drug that has been used successfully to treat billions of humans, livestock and pets. Until recently, the binding site on its Cys-loop receptor target had been a mystery. Recent protein crystal structures, site-directed mutagenesis data and molecular modelling now explain how ivermectin binds to these receptors and reveal why it is selective for invertebrate members of the Cys-loop receptor family. Combining this with emerging genomic information, we are now in a position to predict species sensitivity to ivermectin and better understand the molecular basis of ivermectin resistance. An understanding of the molecular structure of the ivermectin binding site, which is formed at the interface of two adjacent subunits in the transmembrane domain of the receptor, should also aid the development of new lead compounds both as anthelmintics and as therapies for a wide variety of human neurological disorders.

AB - Ivermectin is a gold standard antiparasitic drug that has been used successfully to treat billions of humans, livestock and pets. Until recently, the binding site on its Cys-loop receptor target had been a mystery. Recent protein crystal structures, site-directed mutagenesis data and molecular modelling now explain how ivermectin binds to these receptors and reveal why it is selective for invertebrate members of the Cys-loop receptor family. Combining this with emerging genomic information, we are now in a position to predict species sensitivity to ivermectin and better understand the molecular basis of ivermectin resistance. An understanding of the molecular structure of the ivermectin binding site, which is formed at the interface of two adjacent subunits in the transmembrane domain of the receptor, should also aid the development of new lead compounds both as anthelmintics and as therapies for a wide variety of human neurological disorders.

KW - Amino Acid Sequence

KW - Animals

KW - Antiparasitic Agents

KW - Binding Sites

KW - Crystallography, X-Ray

KW - Cysteine Loop Ligand-Gated Ion Channel Receptors

KW - Humans

KW - Invertebrates

KW - Ivermectin

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Mutagenesis, Site-Directed

KW - Protein Conformation

U2 - 10.1016/j.tips.2012.05.002

DO - 10.1016/j.tips.2012.05.002

M3 - Journal article

C2 - 22677714

SN - 0165-6147

VL - 33

SP - 432

EP - 441

JO - Trends in Pharmacological Sciences

JF - Trends in Pharmacological Sciences

IS - 8

ER -

Ivermectin binding sites in human and invertebrate Cys-loop receptors

Abstract

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