Target Information

Target General Information

Target ID

T97917 (Former ID: TTDR00540)

Target Name

FMLP-related receptor I (FPR2)

Synonyms

RFP; Lipoxin A4 receptor; LXA4 receptor; HM63; G-protein-coupled receptor FPR-Like-1; Formyl peptide receptor-like 1; FPRL1; FPR2; FMLP-R-I

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Gene Name

FPR2

Target Type

Literature-reported target

[1]

Disease

[+] 1 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Function

Low affinity receptor for N-formyl-methionyl peptides, which are powerful neutrophils chemotactic factors. Binding of FMLP to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activates a phosphatidylinositol-calcium second messenger system. The activation of LXA4R could result in an anti-inflammatory outcome counteracting the actions of proinflammatory signals such as LTB4 (leukotrieneB4).

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BioChemical Class

GPCR rhodopsin

UniProt ID

FPR2_HUMAN

Sequence

METNFSTPLNEYEEVSYESAGYTVLRILPLVVLGVTFVLGVLGNGLVIWVAGFRMTRTVT
TICYLNLALADFSFTATLPFLIVSMAMGEKWPFGWFLCKLIHIVVDINLFGSVFLIGFIA
LDRCICVLHPVWAQNHRTVSLAMKVIVGPWILALVLTLPVFLFLTTVTIPNGDTYCTFNF
ASWGGTPEERLKVAITMLTARGIIRFVIGFSLPMSIVAICYGLIAAKIHKKGMIKSSRPL
RVLTAVVASFFICWFPFQLVALLGTVWLKEMLFYGKYKIIDILVNPTSSLAFFNSCLNPM
LYVFVGQDFRERLIHSLPTSLERALSEDSAPTNDTAANSASPPAETELQAM

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3D Structure

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PDB

Drugs and Modes of Action

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Preclinical Drug(s)

[+] 1 Preclinical Drugs

humanin

Drug Info

Preclinical

Alzheimer disease

[2]

Mode of Action

[+] 2 Modes of Action

Agonist

[+] 12 Agonist drugs

humanin

Drug Info

[3]

AG-26

Drug Info

[4]

aspirin triggered lipoxin A4

Drug Info

[5]

aspirin-triggered resolvin D1

Drug Info

[1]

ATLa2

Drug Info

[6]

fMet-Leu-Phe

Drug Info

[7]

LXA4

Drug Info

[8], [9]

PMID22607879CR-(-)-5f

Drug Info

[10]

pyrazolone, 1

Drug Info

[12]

quin-C1

Drug Info

[13]

RvD1-ME

Drug Info

[1]

[3H]resolvin D1

Drug Info

[8]

Antagonist

[+] 2 Antagonist drugs

PMID23788657C1754-31

Drug Info

[11]

quin-C7

Drug Info

[14]

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: Cholesterol

Ligand Info

Structure Description

Cryo-EM structure of formyl peptide receptor 2/lipoxin A4 receptor in complex with Gi

PDB:6OMM

Method

Electron microscopy

Resolution

3.17 Å

Mutation

Yes

[15]

PDB Sequence

GYTVLRILPL

³⁰

VVLGVTFVLG

⁴⁰

VLGNGLVIWV

⁵⁰

AGFRMTRTVT

⁶⁰

TICYLNLALA

⁷⁰

DFSFTATLPF

⁸⁰

LIVSMAMGEK

⁹⁰

WPFGWFLCKL

¹⁰⁰

IHIVVDINLF

¹¹⁰

GSVFLIGFIA

¹²⁰

LDRCICVLHP

¹³⁰

VWAQNHRTVS

¹⁴⁰

LAMKVIVGPW

¹⁵⁰

ILALVLTLPV

¹⁶⁰

FLFLTTVTIP

¹⁷⁰

NGDTYCTFNF

¹⁸⁰

ASWGGTPEER

¹⁹⁰

LKVAITMLTA

²⁰⁰

RGIIRFVIGF

²¹⁰

SLPMSIVAIC

²²⁰

YGLIAAKIHK

²³⁰

KGMIKSSRPL

²⁴⁰

RVLTAVVASF

²⁵⁰

FICWFPFQLV

²⁶⁰

ALLGTVWLKE

²⁷⁰

MLFYGKYKII

²⁸⁰

DILVNPTSSL

²⁹⁰

AFFNSCLNPM

³⁰⁰

LYVFVGQDFR

³¹⁰

ERLIHSL

Residue

Distance (Å)

ILE27

3.731

LEU30

3.740

VAL31

3.971

GLY34

3.633

VAL35

3.638

PHE37

3.780

VAL38

3.756

ILE82

4.210

VAL83

3.830

ALA86

4.023

MET87

4.159

PHE118

3.613

LEU121

3.994

ILE125

3.759

HIS129

3.771

TRP132

3.552

Residue

Distance (Å)

VAL145

3.777

PHE206

4.289

ALA218

3.315

ILE219

4.279

TYR221

4.604

GLY222

3.732

ALA225

3.804

HIS229

3.453

LEU240

3.764

LEU243

4.965

PHE255

4.757

LEU259

3.541

LEU262

3.644

LEU263

4.179

VAL266

3.856

TRP267

4.328

Ligand Name: Pyrazolone, 1

Ligand Info

Structure Description

Structure of the human FPR2-Gi complex with compound C43

PDB:7T6S

Method

Electron microscopy

Resolution

3.00 Å

Mutation

[16]

PDB Sequence

AGYTVLRILP

²⁹

LVVLGVTFVL

³⁹

GVLGNGLVIW

⁴⁹

VAGFRMTRTV

⁵⁹

TTICYLNLAL

⁶⁹

ADFSFTATLP

⁷⁹

FLIVSMAMGE

⁸⁹

KWPFGWFLCK

⁹⁹

LIHIVVDINL

¹⁰⁹

FGSVFLIGFI

¹¹⁹

ALDRCICVLH

¹²⁹

PVWAQNHRTV

¹³⁹

SLAMKVIVGP

¹⁴⁹

WILALVLTLP

¹⁵⁹

VFLFLTTVTI

¹⁶⁹

PNGDTYCTFN

¹⁷⁹

FASWGGTPEE

¹⁸⁹

RLKVAITMLT

¹⁹⁹

ARGIIRFVIG

²⁰⁹

FSLPMSIVAI

²¹⁹

CYGLIAAKIH

²²⁹

KKGMIKSSRP

²³⁹

LRVLTAVVAS

²⁴⁹

FFICWFPFQL

²⁵⁹

VALLGTVWLK

²⁶⁹

EMLFYGKYKI

²⁷⁹

IDILVNPTSS

²⁸⁹

LAFFNSCLNP

²⁹⁹

MLYVFVGQDF

³⁰⁹

RERLIHSL

Residue

Distance (Å)

LEU81

4.364

HIS102

3.487

VAL105

4.156

ASP106

3.167

LEU109

3.872

PHE110

3.472

VAL113

3.877

ARG201

3.280

Residue

Distance (Å)

ARG205

2.864

GLY209

3.763

TRP254

3.573

PHE257

3.463

GLN258

3.441

ALA261

4.384

VAL284

3.545

PHE292

3.401

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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). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

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).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Mas-related G-protein coupled receptor MRG (MAS1L)		22.923 (80/349)	6.20E-07
Mas-related G-protein coupled receptor member F (MRGPRF)		26.316 (30/114)	6.52E-05
Mas-related G-protein coupled receptor member G (MRGPRG)		30.000 (30/100)	1.86E-04
Olfactory receptor 10A6 (OR10A6)	PF13853	27.559 (35/127)	4.81E-04
Olfactory receptor 1C1 (OR1C1)	PF13853	26.020 (51/196)	4.90E-04

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	1.02E-04
Closeness centrality	1.94E-01	Radiality	1.33E+01	Clustering coefficient	3.33E-01
Neighborhood connectivity	8.00E+00	Topological coefficient	2.87E-01	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

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

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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PID Pathway

[+] 1 PID Pathways

Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling

Reactome

[+] 2 Reactome Pathways

G alpha (q) signalling events

G alpha (i) signalling events

WikiPathways

[+] 5 WikiPathways

GPCRs, Class A Rhodopsin-like

Gastrin-CREB signalling pathway via PKC and MAPK

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

References

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REF 1

Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. Am J Pathol. 2012 May;180(5):2018-27.

REF 2

ClinicalTrials.gov (NCT03431844) Humanin Isoforms in Cardiac Muscle and Blood Plasma and Major Complications After Cardiac Operation. U.S. National Institutes of Health.

REF 3

N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun. 2004 Nov 5;324(1):255-61.

REF 4

Identification of novel small-molecule agonists for human formyl peptide receptors and pharmacophore models of their recognition. Mol Pharmacol. 2010 Feb;77(2):159-70.

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 223).

REF 6

Novel 3-oxa lipoxin A4 analogues with enhanced chemical and metabolic stability have anti-inflammatory activity in vivo. J Med Chem. 2004 Apr 8;47(8):2157-65.

REF 7

Multiple domains of the N-formyl peptide receptor are required for high-affinity ligand binding. Construction and analysis of chimeric N-formyl peptide receptors. J Biol Chem. 1993 Aug 25;268(24):18167-75.

REF 8

Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1660-5.

REF 9

Lipoxin recognition sites. Specific binding of labeled lipoxin A4 with human neutrophils. J Biol Chem. 1992 Aug 15;267(23):16168-76.

REF 10

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists. Bioorg Med Chem. 2012 Jun 15;20(12):3781-92.

REF 11

Selective agonists and antagonists of formylpeptide receptors: duplex flow cytometry and mixture-based positional scanning libraries. Mol Pharmacol. 2013 Sep;84(3):314-24.

REF 12

Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3713-8.

REF 13

A novel nonpeptide ligand for formyl peptide receptor-like 1. Mol Pharmacol. 2004 Nov;66(5):1213-22.

REF 14

Pharmacological characterization of a novel nonpeptide antagonist for formyl peptide receptor-like 1. Mol Pharmacol. 2007 Oct;72(4):976-83.

REF 15

Structure of formylpeptide receptor 2-G(i) complex reveals insights into ligand recognition and signaling. Nat Commun. 2020 Feb 14;11(1):885.

REF 16

Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2. Nat Commun. 2022 Feb 25;13(1):1054.

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