Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors : Unique role of halogen bonding revealed. / Rohde, Line Aagot Hede; Ahring, Philip Kiær; Jensen, Marianne Lerbech; Nielsen, Elsebet Østergaard; Peters, Dan; Helgstrand, Charlotte; Krintel, Christian; Harpsøe, Kasper; Gajhede, Michael; Kastrup, Jette Sandholm; Balle, Thomas.

In: The Journal of Biological Chemistry, Vol. 287, No. 6, 03.02.2012, p. 4248-4259.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Rohde, LAH, Ahring, PK, Jensen, ML, Nielsen, EØ, Peters, D, Helgstrand, C, Krintel, C, Harpsøe, K, Gajhede, M, Kastrup, JS & Balle, T 2012, 'Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed', The Journal of Biological Chemistry, vol. 287, no. 6, pp. 4248-4259. https://doi.org/10.1074/jbc.M111.292243

APA

Rohde, L. A. H., Ahring, P. K., Jensen, M. L., Nielsen, E. Ø., Peters, D., Helgstrand, C., ... Balle, T. (2012). Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed. The Journal of Biological Chemistry, 287(6), 4248-4259. https://doi.org/10.1074/jbc.M111.292243

Vancouver

Rohde LAH, Ahring PK, Jensen ML, Nielsen EØ, Peters D, Helgstrand C et al. Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed. The Journal of Biological Chemistry. 2012 Feb 3;287(6):4248-4259. https://doi.org/10.1074/jbc.M111.292243

Author

Rohde, Line Aagot Hede ; Ahring, Philip Kiær ; Jensen, Marianne Lerbech ; Nielsen, Elsebet Østergaard ; Peters, Dan ; Helgstrand, Charlotte ; Krintel, Christian ; Harpsøe, Kasper ; Gajhede, Michael ; Kastrup, Jette Sandholm ; Balle, Thomas. / Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors : Unique role of halogen bonding revealed. In: The Journal of Biological Chemistry. 2012 ; Vol. 287, No. 6. pp. 4248-4259.

Bibtex

@article{bb28c967c1dd40ce854217b0c0def4a3,
title = "Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors: Unique role of halogen bonding revealed",
abstract = "The a4{\ss}2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4{\ss}2 agonists is lacking. Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4{\ss}2 and the acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4{\ss}2 receptors. Crystal structures of five agonists with efficacies at a4{\ss}2 from 21-76{\%} were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong inter-subunit anchoring.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Rohde, {Line Aagot Hede} and Ahring, {Philip Ki{\ae}r} and Jensen, {Marianne Lerbech} and Nielsen, {Elsebet {\O}stergaard} and Dan Peters and Charlotte Helgstrand and Christian Krintel and Kasper Harps{\o}e and Michael Gajhede and Kastrup, {Jette Sandholm} and Thomas Balle",
note = "Keywords: acetylcholine binding protein; lymnaea stagnalis; crystal structure; nicotinic acetylcholine receptor; agonist ; efficacy",
year = "2012",
month = "2",
day = "3",
doi = "10.1074/jbc.M111.292243",
language = "English",
volume = "287",
pages = "4248--4259",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology, Inc.",
number = "6",

}

RIS

TY - JOUR

T1 - Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine alpha4beta2 receptors

T2 - Unique role of halogen bonding revealed

AU - Rohde, Line Aagot Hede

AU - Ahring, Philip Kiær

AU - Jensen, Marianne Lerbech

AU - Nielsen, Elsebet Østergaard

AU - Peters, Dan

AU - Helgstrand, Charlotte

AU - Krintel, Christian

AU - Harpsøe, Kasper

AU - Gajhede, Michael

AU - Kastrup, Jette Sandholm

AU - Balle, Thomas

N1 - Keywords: acetylcholine binding protein; lymnaea stagnalis; crystal structure; nicotinic acetylcholine receptor; agonist ; efficacy

PY - 2012/2/3

Y1 - 2012/2/3

N2 - The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking. Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4ß2 and the acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4ß2 receptors. Crystal structures of five agonists with efficacies at a4ß2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong inter-subunit anchoring.

AB - The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking. Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4ß2 and the acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4ß2 receptors. Crystal structures of five agonists with efficacies at a4ß2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong inter-subunit anchoring.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1074/jbc.M111.292243

DO - 10.1074/jbc.M111.292243

M3 - Journal article

C2 - 22170047

VL - 287

SP - 4248

EP - 4259

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -

ID: 35936290