Target Information

Target General Information

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Target ID

T15439 (Former ID: TTDNC00518)

Target Name

C5a anaphylatoxin chemotactic receptor (C5AR1)

Synonyms

CD88; C5aR; C5a-R; C5a anaphylatoxin chemotactic receptor 1; C5R1

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Gene Name

C5AR1

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Vasculitis [ICD-11: 4A44]

Function

The ligand interacts with at least two sites on the receptor: a high-affinity site on the extracellular N-terminus, and a second site in the transmembrane region which activates downstream signaling events. Receptor activation stimulates chemotaxis, granule enzyme release, intracellular calcium release and superoxide anion production. Receptor for the chemotactic and inflammatory peptide anaphylatoxin C5a.

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BioChemical Class

GPCR rhodopsin

UniProt ID

C5AR1_HUMAN

Sequence

MDSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVW
VTAFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLNM
YASILLLATISADRFLLVFKPIWCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREE
YFPPKVLCGVDYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKT
LKVVVAVVASFFIFWLPYQVTGIMMSFLEPSSPTFLLLKKLDSLCVSFAYINCCINPIIY
VVAGQGFQGRLRKSLPSLLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV

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3D Structure

Click to Show 3D Structure of This Target

PDB

HIT2.0 ID

T27LTU

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Avacopan

Drug Info

Approved

Anca-associated vasculitis

[2]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

PMX-53

Drug Info

Phase 2

Atopic dermatitis

[3], [4]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

NN8209

Drug Info

Discontinued in Phase 2

Rheumatoid arthritis

[5]

NN8210

Drug Info

Discontinued in Phase 1

Rheumatoid arthritis

[6]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

PMX205

Drug Info

Preclinical

Central nervous system disease

[7]

Mode of Action

[+] 2 Modes of Action

Antagonist

[+] 5 Antagonist drugs

Avacopan

Drug Info

[1]

PMX205

Drug Info

[10]

NDT9520492

Drug Info

[12]

RPR121154

Drug Info

[11]

W54011

Drug Info

[13]

Modulator

[+] 4 Modulator drugs

PMX-53

Drug Info

[8]

NN8209

Drug Info

[9]

NN8210

Drug Info

[9]

C5aR pepducins

Drug Info

[11]

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: Oleic acid

Ligand Info

Structure Description

Crystal structure of thermostabilised human C5a anaphylatoxin chemotactic receptor 1 (C5aR) in complex with NDT9513727

PDB:5O9H

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

Yes

[14]

PDB Sequence

NTLRVPDILA

⁴⁰

LVIFAVVFLV

⁵⁰

GVLGNALVVW

⁶⁰

VTAFEAKRTI

⁷⁰

NAIWFLNLAV

⁸⁰

ADFLACLALP

⁹⁰

ALFTSIVQHH

¹⁰⁰

HWPFGGAACS

¹¹⁰

ILPSLILLNM

¹²⁰

YASILLLATI

¹³⁰

SADRFLLVFK

¹⁴⁰

PAWCQRFRGA

¹⁵⁰

GLAWILCAVA

¹⁶⁰

WGLALLLTIP

¹⁷⁰

SALYRVVREE

¹⁸⁰

YFPPKVLCGV

¹⁹⁰

DHDKRRERAV

²⁰²

AIVRLVLGFL

²¹²

WPLLTLTICY

²²²

TFILLRTWSA

²³²

RETRSTKTLK

²⁴²

VVVAVVASFF

²⁵²

IFWLPYQVTG

²⁶²

IMMSFLEPSS

²⁷²

PTFLLLKKLD

²⁸²

SLCVSFAYIN

²⁹²

CCINPIIYVV

³⁰²

AGQGFQKSLP

³¹⁶

ELLREVLTEE

³²⁶

SVVR

Residue

Distance (Å)

ILE38

4.658

LEU41

4.193

VAL42

3.500

ALA45

4.358

VAL46

3.765

ALA63

3.626

ALA66

4.314

LYS67

4.796

ILE70

4.738

TRP74

3.802

LEU76

4.650

VAL80

4.015

LEU84

4.147

PRO90

3.746

PHE93

4.005

THR94

3.669

VAL97

4.120

GLN98

2.343

ALA128

4.330

THR129

4.271

SER131

4.539

ALA132

3.486

ASP133

3.940

PHE135

3.279

LEU136

3.779

PHE139

3.950

LYS140

3.556

TRP143

3.460

PHE147

4.480

ARG148

3.846

GLY149

3.792

GLY151

3.887

LEU152

3.912

ALA153

3.953

TRP154

4.023

ILE155

4.367

LEU156

3.930

ALA158

3.583

VAL159

3.923

GLY162

3.423

LEU163

3.950

LEU166

4.739

ALA201

4.089

Residue

Distance (Å)

ILE204

3.987

VAL205

4.667

LEU207

3.867

VAL208

4.605

PHE211

4.253

LEU212

3.880

TRP213

4.649

LEU215

3.988

LEU216

3.423

THR217

3.864

LEU218

3.435

THR219

3.831

ILE220

3.488

CYS221

4.012

TYR222

4.012

THR223

3.617

PHE224

3.242

LEU226

3.681

LEU227

3.695

ARG228

3.659

THR229

4.915

TRP230

3.149

SER231

3.389

LYS242

3.413

VAL245

3.672

ALA246

3.727

VAL248

4.010

ALA249

3.905

SER250

3.800

PHE252

3.688

ILE253

3.416

PHE254

4.112

LEU256

4.490

VAL260

3.870

ILE263

4.087

MET264

3.929

ILE291

3.907

CYS294

4.301

ILE295

3.550

ILE298

4.072

ILE299

3.988

VAL302

3.817

ALA303

4.363

Ligand Name: n,n-Bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1h-imidazole-5-methanamine

Ligand Info

Structure Description

Crystal structure of thermostabilised human C5a anaphylatoxin chemotactic receptor 1 (C5aR) in complex with NDT9513727

PDB:5O9H

Method

X-ray diffraction

Resolution

2.70 Å

Mutation

Yes

[14]

PDB Sequence

NTLRVPDILA

⁴⁰

LVIFAVVFLV

⁵⁰

GVLGNALVVW

⁶⁰

VTAFEAKRTI

⁷⁰

NAIWFLNLAV

⁸⁰

ADFLACLALP

⁹⁰

ALFTSIVQHH

¹⁰⁰

HWPFGGAACS

¹¹⁰

ILPSLILLNM

¹²⁰

YASILLLATI

¹³⁰

SADRFLLVFK

¹⁴⁰

PAWCQRFRGA

¹⁵⁰

GLAWILCAVA

¹⁶⁰

WGLALLLTIP

¹⁷⁰

SALYRVVREE

¹⁸⁰

YFPPKVLCGV

¹⁹⁰

DHDKRRERAV

²⁰²

AIVRLVLGFL

²¹²

WPLLTLTICY

²²²

TFILLRTWSA

²³²

RETRSTKTLK

²⁴²

VVVAVVASFF

²⁵²

IFWLPYQVTG

²⁶²

IMMSFLEPSS

²⁷²

PTFLLLKKLD

²⁸²

SLCVSFAYIN

²⁹²

CCINPIIYVV

³⁰²

AGQGFQKSLP

³¹⁶

ELLREVLTEE

³²⁶

SVVR

Residue

Distance (Å)

ILE124

3.679

LEU125

3.408

ALA128

3.591

THR129

3.546

ALA132

4.846

LEU156

3.280

VAL159

3.679

ALA160

3.732

Residue

Distance (Å)

LEU163

3.479

VAL208

4.924

LEU209

3.541

TRP213

2.980

PRO214

3.610

THR217

3.170

LEU218

4.445

Click to View More Binding Site Information of This Target with Different Ligands

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 Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). 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 Tissue Distribution 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 Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

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 Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Mas-related G-protein coupled receptor MRG (MAS1L)		26.667 (84/315)	3.57E-11
Mas-related G-protein coupled receptor member F (MRGPRF)		25.879 (81/313)	1.13E-10
Olfactory receptor 2AG2 (OR2AG2)	PF13853	22.973 (68/296)	7.07E-06
Olfactory receptor 2F1 (OR2F1)	PF13853	23.891 (70/293)	1.29E-04
Olfactory receptor 4K1 (OR4K1)	PF13853	23.469 (69/294)	2.25E-04
Olfactory receptor 5M11 (OR5M11)	PF13853	30.556 (33/108)	2.35E-04
Olfactory receptor 2AG1 (OR2AG1)	PF13853	23.179 (70/302)	2.38E-04
Olfactory receptor 2D3 (OR2D3)	PF13853	23.322 (66/283)	1.00E-03
Olfactory receptor 2F2 (OR2F2)	PF13853	23.630 (69/292)	1.00E-03
Olfactory receptor 10A6 (OR10A6)	PF13853	27.132 (35/129)	1.00E-03
Mas-related G-protein coupled receptor member G (MRGPRG)		31.250 (40/128)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Complement and coagulation cascades	hsa04610	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Neutrophil extracellular trap formation	hsa04613	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	3	Degree centrality	3.22E-04	Betweenness centrality	7.33E-04
Closeness centrality	2.02E-01	Radiality	1.35E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	5.33E+01	Topological coefficient	3.33E-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

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 Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Neuroactive ligand-receptor interaction

Complement and coagulation cascades

Staphylococcus aureus infection

Panther Pathway

[+] 1 Panther Pathways

Inflammation mediated by chemokine and cytokine signaling pathway

Reactome

[+] 2 Reactome Pathways

Peptide ligand-binding receptors

G alpha (i) signalling events

WikiPathways

[+] 5 WikiPathways

Complement and Coagulation Cascades

Human Complement System

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

References

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REF 1

Clinical pipeline report, company report or official report of ChemoCentryx.

REF 2

FDA Approved Drug Products from FDA Official Website. 2021. Application Number: 214487.

REF 3

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. (Ligand id: 579).

REF 4

PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol Pharmacol. 2011 Jun;79(6):1005-13.

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022053)

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800036376)

REF 7

Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice. ACS Omega. 2020 Jan 30;5(5):2345-2354.

REF 8

Company report (Arana Therapeutics)

REF 9

Complement in immune and inflammatory disorders: therapeutic interventions. J Immunol. 2013 Apr 15;190(8):3839-47.

REF 10

Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice. Sci Rep. 2018 May 25;8(1):8101.

REF 11

REF 12

Molecular characterization of the gerbil C5a receptor and identification of a transmembrane domain V amino acid that is crucial for small molecule ... J Biol Chem. 2005 Dec 9;280(49):40617-23.

REF 13

Identification of a potent and orally active non-peptide C5a receptor antagonist. J Biol Chem. 2002 Dec 20;277(51):49403-7.

REF 14

Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727. Nature. 2018 Jan 3;553(7686):111-114.

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