Target Information

Target General Information

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Target ID

T15571 (Former ID: TTDR00565)

Target Name

5-HT 5A receptor (HTR5A)

Synonyms

Serotonin receptor 5A; 5-hydroxytryptamine receptor 5A; 5-HT5A; 5-HT-5A; 5-HT-5; 5-HT 5A

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Gene Name

HTR5A

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Pituitary gland disorder [ICD-11: 5A60-5A61]

Function

The activity of this receptor is mediated by G proteins. This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen.

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BioChemical Class

GPCR rhodopsin

UniProt ID

5HT5A_HUMAN

Sequence

MDLPVNLTSFSLSTPSPLETNHSLGKDDLRPSSPLLSVFGVLILTLLGFLVAATFAWNLL
VLATILRVRTFHRVPHNLVASMAVSDVLVAALVMPLSLVHELSGRRWQLGRRLCQLWIAC
DVLCCTASIWNVTAIALDRYWSITRHMEYTLRTRKCVSNVMIALTWALSAVISLAPLLFG
WGETYSEGSEECQVSREPSYAVFSTVGAFYLPLCVVLFVYWKIYKAAKFRVGSRKTNSVS
PISEAVEVKDSAKQPQMVFTVRHATVTFQPEGDTWREQKEQRAALMVGILIGVFVLCWIP
FFLTELISPLCSCDIPAIWKSIFLWLGYSNSFFNPLIYTAFNKNYNSAFKNFFSRQH

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Metergolin

Drug Info

Approved

Hyperprolactinaemia

[2]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 5 Antagonist drugs

Metergolin

Drug Info

[1]

bufotenine

Drug Info

[6]

MPDT

Drug Info

[7]

SB 699551

Drug Info

[9]

SB-699551-A

Drug Info

[10]

Inhibitor

[+] 16 Inhibitor drugs

(+/-)-nantenine

Drug Info

[3]

3,4-dihydroquinazolin-2-amine hydrobromide

Drug Info

[4]

4-ethyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

4-methyl-N-propyl-3,4-dihydroquinazolin-2-amine

Drug Info

[5]

4-propyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

5,6-dichloro-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

5-chloro-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

5-chloro-4-ethyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

5-chloro-4-methyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

8-chloro-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

8-methoxy-4-methyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

METHIOTHEPIN

Drug Info

[8]

N,4-dimethyl-3,4-dihydroquinazolin-2-amine

Drug Info

[5]

N,N-dimethyl-3,4-dihydroquinazolin-2-amine

Drug Info

[4]

N-butyl-4-methyl-3,4-dihydroquinazolin-2-amine

Drug Info

[5]

SEROTONIN

Drug Info

[11]

Agonist

[+] 6 Agonist drugs

5-CT

Drug Info

[6]

EDMT

Drug Info

[7]

lysergic acid

Drug Info

[6]

TFMPP

Drug Info

[12]

[125I]LSD

Drug Info

[13]

[3H]5-CT

Drug Info

[13]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Methylergonovine

Ligand Info

Structure Description

CryoEM structure of Go-coupled 5-HT5AR in complex with Methylergometrine

PDB:7UM7

Method

Electron microscopy

Resolution

2.75 Å

Mutation

[14]

PDB Sequence

GVLILTLLGF

⁴⁹

LVAATFAWNL

⁵⁹

LVLATILRVR

⁶⁹

TFHRVPHNLV

⁷⁹

ASMAVSDVLV

⁸⁹

AALVMPLSLV

⁹⁹

HELSGRRWQL

¹⁰⁹

GRRLCQLWIA

¹¹⁹

CDVLCCTASI

¹²⁹

WNVTAIALDR

¹³⁹

YWSITRPMEY

¹⁴⁹

TLRTRKCVSN

¹⁵⁹

VMIALTWALS

¹⁶⁹

AVISLAPLLF

¹⁷⁹

GEECQVSREP

¹⁹⁸

SYAVFSTVGA

²⁰⁸

FYLPLCVVLF

²¹⁸

VYWKIYKAAK

²²⁸

FRVEQKEQRA

²⁸³

ALMVGILIGV

²⁹³

FVLCWIPFFL

³⁰³

TELISPLCSC

³¹³

DIPAIWKSIF

³²³

LWLGYSNSFF

³³³

NPLIYTAFNK

³⁴³

NYNSAF

Residue

Distance (Å)

TRP117

3.496

ILE118

3.469

ASP121

2.983

VAL122

3.718

CYS125

3.536

THR126

3.002

CYS192

4.268

VAL194

4.339

SER204

3.720

Residue

Distance (Å)

THR205

4.909

ALA208

4.436

TRP298

3.805

PHE301

3.908

PHE302

4.133

GLU305

4.714

LEU324

3.253

TYR328

3.994

Ligand Name: Lisuride

Ligand Info

Structure Description

CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride

PDB:7UM6

Method

Electron microscopy

Resolution

2.79 Å

Mutation

Yes

[14]

PDB Sequence

GVLILTLLGF

⁴⁹

LVAATFAWNL

⁵⁹

LVLATILRVR

⁶⁹

TFHRVPHNLV

⁷⁹

ASMAVSDVLV

⁸⁹

AALVMPLSLV

⁹⁹

HELSGRRWQL

¹⁰⁹

GRRLCQLWIA

¹¹⁹

CDVLCCTASI

¹²⁹

WNVTAIALDR

¹³⁹

YWSITRPMEY

¹⁴⁹

TLRTRKCVSN

¹⁵⁹

VMIALTWALS

¹⁶⁹

AVISLAPLLF

¹⁷⁹

GEECQVSREP

¹⁹⁸

SYAVFSTVGA

²⁰⁸

FYLPLCVVLF

²¹⁸

VYWKIYKAAK

²²⁸

FRVWREQKEQ

²⁸¹

RAALMVGILI

²⁹¹

GVFVLCWIPF

³⁰¹

FLTELISPLC

³¹¹

SCDIPAIWKS

³²¹

IFLWLGYSNS

³³¹

FFNPLIYTAF

³⁴¹

NKNYNSAF

Residue

Distance (Å)

TRP117

3.504

ILE118

4.556

ASP121

2.803

VAL122

3.960

CYS125

3.599

THR126

3.413

CYS192

3.652

GLN193

4.635

VAL194

4.128

Residue

Distance (Å)

SER204

3.364

THR205

4.804

ALA208

4.171

TRP298

4.509

PHE301

3.676

PHE302

4.402

GLU305

4.460

LEU324

3.287

TYR328

4.570

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Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 1A2 (OR1A2)	PF13853	22.000 (44/200)	2.70E-05
Olfactory receptor 3A1 (OR3A1)	PF13853	29.688 (38/128)	1.35E-04
Olfactory receptor 4D5 (OR4D5)	PF13853	26.316 (30/114)	4.00E-03

KEGG Pathway	Pathway ID	Affiliated Target
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Serotonergic synapse	hsa04726	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Calcium signaling pathway

Neuroactive ligand-receptor interaction

Serotonergic synapse

Panther Pathway

[+] 1 Panther Pathways

Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway

Reactome

[+] 2 Reactome Pathways

Serotonin receptors

G alpha (i) signalling events

WikiPathways

[+] 4 WikiPathways

Monoamine GPCRs

GPCRs, Class A Rhodopsin-like

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Cloning and characterisation of the human 5-HT5A serotonin receptor. FEBS Lett. 1994 Dec 5;355(3):242-6.

REF 2

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 3

Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.

REF 4

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: structure-activity relationship elucidation. Bioorg Med Chem Lett. 2008 Jan 1;18(1):256-61.

REF 5

Cyclic guanidines as dual 5-HT5A/5-HT7 receptor ligands: optimising brain penetration. Bioorg Med Chem Lett. 2008 Jan 1;18(1):262-6.

REF 6

Expression of functional mouse 5-HT5A serotonin receptor in the methylotrophic yeast Pichia pastoris: pharmacological characterization and localization. FEBS Lett. 1995 Dec 27;377(3):451-6.

REF 7

2-Substituted tryptamines: agents with selectivity for 5-HT(6) serotonin receptors. J Med Chem. 2000 Mar 9;43(5):1011-8.

REF 8

Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7). J Med Chem. 2003 Jul 3;46(14):2795-812.

REF 9

Discovery of a potent and selective 5-ht5A receptor antagonist by high-throughput chemistry. Bioorg Med Chem Lett. 2005 Sep 15;15(18):4014-8.

REF 10

5-ht5A receptors as a therapeutic target. Pharmacol Ther. 2006 Sep;111(3):707-14.

REF 11

Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity. J Med Chem. 2008 Jul 24;51(14):4150-69.

REF 12

Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol Pharmacol. 1993 Mar;43(3):313-9.

REF 13

Human 5-HT(5) receptors: the 5-HT(5A) receptor is functional but the 5-HT(5B) receptor was lost during mammalian evolution. Eur J Pharmacol. 2001 Apr 27;418(3):157-67.

REF 14

Inactive and active state structures template selective tools for the human 5-HT(5A) receptor. Nat Struct Mol Biol. 2022 Jul;29(7):677-687.

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