Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site

被引:17
作者
Brams, Marijke [1 ]
Govaerts, Cedric [2 ]
Kambara, Kumiko [3 ]
Price, Kerry L. [4 ]
Spurny, Radovan [1 ]
Gharpure, Anant [5 ,6 ]
Pardon, Els [7 ,8 ]
Evans, Genevieve L. [1 ]
Bertrand, Daniel [3 ]
Lummis, Sarah C. R. [4 ]
Hibbs, Ryan E. [5 ,6 ]
Steyaert, Jan [7 ,8 ]
Ulens, Chris [1 ]
机构
[1] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Struct Neurobiol, Fac Med, Leuven, Belgium
[2] Univ Libre Bruxelles, Ctr Struct Biol & Bioinformat, Lab Struct & Funct Biol Membranes, Brussels, Belgium
[3] HiQscreen, Geneva, Switzerland
[4] Univ Cambridge, Dept Biochem, Cambridge, England
[5] Univ Texas Southwestern Med Ctr Dallas, Dept Neurosci, Dallas, TX 75390 USA
[6] Univ Texas Southwestern Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA
[7] Vrije Univ Brussel, Struct Biol Brussels, Brussels, Belgium
[8] VIB, VIB VUB Ctr Struct Biol, Brussels, Belgium
来源
ELIFE | 2020年 / 9卷
基金
美国国家卫生研究院;
关键词
X-RAY-STRUCTURE; NICOTINIC ACETYLCHOLINE-RECEPTOR; ALLOSTERIC BINDING-SITE; CRYSTAL-STRUCTURE; EXTRACELLULAR DOMAIN; GATING MECHANISM; STRUCTURAL BASIS; ACTIVATION; COMPLEX; CHIMERA;
D O I
10.7554/eLife.51511
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.
引用
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页数:19
相关论文
共 68 条
[1]   PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].
Adams, Paul D. ;
Afonine, Pavel V. ;
Bunkoczi, Gabor ;
Chen, Vincent B. ;
Davis, Ian W. ;
Echols, Nathaniel ;
Headd, Jeffrey J. ;
Hung, Li-Wei ;
Kapral, Gary J. ;
Grosse-Kunstleve, Ralf W. ;
McCoy, Airlie J. ;
Moriarty, Nigel W. ;
Oeffner, Robert ;
Read, Randy J. ;
Richardson, David C. ;
Richardson, Jane S. ;
Terwilliger, Thomas C. ;
Zwart, Peter H. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221
[2]   X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors [J].
Althoff, Thorsten ;
Hibbs, Ryan E. ;
Banerjee, Surajit ;
Gouaux, Eric .
NATURE, 2014, 512 (7514) :333-+
[3]   Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor [J].
Basak, Sandip ;
Gicheru, Yvonne ;
Rao, Shanlin ;
Sansom, Mark S. P. ;
Chakrapani, Sudha .
NATURE, 2018, 563 (7730) :270-+
[4]  
Belelli D, 1995, MOL PHARMACOL, V48, P1054
[5]   Allosteric modulation of nicotinic acetylcholine receptors [J].
Bertrand, Daniel ;
Gopalakrishnan, Murali .
BIOCHEMICAL PHARMACOLOGY, 2007, 74 (08) :1155-1163
[6]   X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation [J].
Bocquet, Nicolas ;
Nury, Hugues ;
Baaden, Marc ;
Le Poupon, Chantal ;
Changeux, Jean-Pierre ;
Delarue, Marc ;
Corringer, Pierre-Jean .
NATURE, 2009, 457 (7225) :111-114
[7]   Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors [J].
Brejc, K ;
van Dijk, WJ ;
Klaassen, RV ;
Schuurmans, M ;
van der Oost, J ;
Smit, AB ;
Sixma, TK .
NATURE, 2001, 411 (6835) :269-276
[8]   Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant [J].
Celie, PHN ;
Kasheverov, IE ;
Mordvintsev, DY ;
Hogg, RC ;
van Nierop, P ;
van Elk, R ;
van Rossum-Fikkert, SE ;
Zhmak, MN ;
Bertrand, D ;
Tsetlin, V ;
Sixma, TK ;
Smit, AB .
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2005, 12 (07) :582-588
[9]   The role of loop 5 in acetylcholine receptor channel gating [J].
Chakrapani, S ;
Bailey, TD ;
Auerbach, A .
JOURNAL OF GENERAL PHYSIOLOGY, 2003, 122 (05) :521-539
[10]   Structural basis of neurosteroid anesthetic action on GABAA receptors [J].
Chen, Qiang ;
Wells, Marta M. ;
Arjunan, Palaniappa ;
Tillman, Tommy S. ;
Cohen, Aina E. ;
Xu, Yan ;
Tang, Pei .
NATURE COMMUNICATIONS, 2018, 9