Structural Basis for Molecular Recognition at Serotonin Receptors

Wang, Chong; Jiang, Yi; Ma, Jinming; Wu, Huixian; Wacker, Daniel; Katritch, Vsevolod; Han, Gye Won; Liu, Wei; Huang, Xi Ping; Vardy, Eyal; McCorvy, John D.; Gao, Xiang; Zhou, Xin; Melcher, Karsten; Zhang, Chenghai; Bai, Fang; Yang, Huaiyu; Yang, Linlin; Jiang, Hualiang; Roth, Bryan L.; Cherezov, Vadim; Stevens, Raymond C.; Xu, H. Eric

doi:10.1126/science.1232807

Cited by 473 publications

(527 citation statements)

References 44 publications

(45 reference statements)

Supporting

Mentioning

495

Contrasting

Order By: Relevance

“…Having solved in part some of the most stringent difficulties of GPCR crystallography, the number of receptor structures is rapidly growing. Thus, 9 structures from the former list of 15 reported in [19] were published just in 2012, while two new class A-ones [37,38] and, for the first time [39], one not belonging to this family but to the Frizzled class [12] and two to class B [16,33] were reported in 2013. At the time of writing, the first structures of the 7TM domains of two class C receptors have just been published [42,11].…”

Section: Methodsmentioning

confidence: 99%

The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

Cruz-Barbosa

Vellido

Giraldo

2014

Med Biol Eng Comput

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are integral cell membrane proteins of relevance for pharmacology. The tertiary structure of the transmembrane domain, a gate to the study of protein functionality, is unknown for almost all members of class C GPCRs, which are the target of the current study. As a result, their investigation must often rely on alignments of their amino acid sequences. Sequence alignment entails the risk of missing relevant information. Various approaches have attempted to circumvent this risk through alignment-free transformations of the sequences on the basis of different amino acid physicochemical properties. In this paper, we use several of these alignment-free methods, as well as a basic amino acid composition representation, to transform the available sequences. Novel semi-supervised statistical machine learning methods are then used to discriminate the different class C GPCRs types from the transformed data. This approach is relevant due to the existence of orphan proteins to which type labels should be assigned in a process of deorphanization or reverse pharmacology. The reported experiments show that the proposed techniques provide accurate classification even in settings of extreme class-label scarcity and that fair accuracy can be achieved even with very simple transformation strategies that ignore the sequence ordering.

show abstract

Section: Methodsmentioning

confidence: 99%

The influence of alignment-free sequence representations on the semi-supervised classification of class C G protein-coupled receptors

Cruz-Barbosa

Vellido

Giraldo

2014

Med Biol Eng Comput

View full text Add to dashboard Cite

show abstract

“…The 5-HT 1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Table 1), which is a selective 5-HT 1A partial agonist. Likewise, 5-HT 1B and 5-HT 1D receptors represent canonical targets for antimigraine medications including various ergots (e.g., ergotamine, dihydroergotamine, and methysergide) as well as the more selective tryptans (e.g., sumatryptan and analogs) (18,19). No selective 5-HT 1E drugs exist and though selective 5-HT 1F drugs have been developed, none of them have yet been approved by the FDA (Table 1).…”

Section: Serotonin Receptors and Signal Transductionmentioning

confidence: 99%

Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs

Meltzer¹,

Roth²

2013

J. Clin. Invest.

Self Cite

103

View full text Add to dashboard Cite

Serotonin (5-hydroxytryptamine, or 5-HT) receptors mediate a plethora of physiological phenomena in the brain and the periphery. Additionally, serotonergic dysfunction has been implicated in nearly every neuropsychiatric disorder. The effects of serotonin are mediated by fourteen GPCRs. Both the therapeutic actions and side effects of commonly prescribed drugs are frequently due to nonspecific actions on various 5-HT receptor subtypes. For more than 20 years, the search for clinically efficacious drugs that selectively target 5-HT receptor subtypes has been only occasionally successful. This review provides an overview of 5-HT receptor pharmacology and discusses two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, which target the 5HT 2C and 5HT 2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively. Serotonin receptors and signal transductionSerotonin, which was known to be the principal vasoconstricting substance found in serum, was chemically identified as 5-hydroxytryptamine by Rapport and colleagues in 1948 (1). Although the effects of serotonin on smooth muscle and other peripheral organs were long appreciated, it wasn't until its structural similarity to lysergic acid diethylamide (LSD) was noted that serotonin and its receptors were linked to neurotransmission (2). Distinct serotonin receptor subtypes were proposed in 1957 (3), with the 5-HT1 receptors having high affinity for serotonin and the 5-HT2 receptors having relatively low affinity for 5-HT. The so-called 5-HT1 and 5-HT2 receptors identified pharmacologically by Gaddum and colleagues (3) roughly correspond to what are now known as the 5-HT 1 and 5-HT 2 families of receptors ( Figure 1).With the development of radioligand-binding technology, multiple distinct serotonin receptors were identified based principally on their differential radioligand-binding properties. Following the cloning of the β-adrenergic receptor (4), 5-HT 1A (5), the first socalled orphan GPCR, was cloned by Brian Kobilka in collaboration with Marc Caron and others (6, 7). In rapid succession, the large family of G protein-coupled serotonin receptors we now appreciate were identified by molecular cloning technology and characterized by pharmacological and biochemical studies (8, 9), including 5-HT 1B/1D (10) and 5-HT 1E (11), as well as 5-HT 2A (12, 13) and 5-HT 2C (14, 15), which have lower affinities for 5-HT than the other serotonin receptors. The 5-HT 4 receptor was also one of the early 5-HT receptor subtypes identified mainly by radioligand binding and pharmacological studies (refs. 16, 17, and see Figure 1).In terms of signal transduction and pharmacology, we now know that all members of the 5-HT 1 family are intronless and couple to the Gi family of heterotrimeric G proteins -in keeping with the original description of the 5-HT 1A receptor (7). The 5-HT 1 family of receptors has been successfully exploited for the treatment of anxiety and depression with the development of drugs like buspirone (Tabl...

show abstract

“…Class A GPCRs are thought to have a common topology that includes an extracellular N terminus, a transmembrane core formed by a bundle of seven transmembrane ␣-helices (TMH1-7), three extracellular (EC) and three intracellular (IC) loops that connect these helices, and an intracellular C terminus that begins with a short amphipathic helix lying parallel to the membrane (3)(4)(5)(6). Physiologically, GPCRs are activated by ligands (extracellular and membrane-based) that enable the receptors to interact with and activate distinct sets of heterotrimeric G proteins (G␣␤␥), as well as ␤-arrestins (7,8).…”

mentioning

confidence: 99%