Target Information

Target General Information

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Target ID

T47081 (Former ID: TTDS00323)

Target Name

Rotamase A (PPIA)

Synonyms

PPIA; Cyclophilin A; CyPA

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Gene Name

PPIA

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Nutritional deficiency [ICD-11: 5B50-5B71]

Function

Ppiases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.

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BioChemical Class

Cis-trans-isomerases

UniProt ID

PPIA_HUMAN

EC Number

EC 5.2.1.8

Sequence

MVNPTVFFDIAVDGEPLGRVSFELFADKVPKTAENFRALSTGEKGFGYKGSCFHRIIPGF
MCQGGDFTRHNGTGGKSIYGEKFEDENFILKHTGPGILSMANAGPNTNGSQFFICTAKTE
WLDGKHVVFGKVKEGMNIVEAMERFGSRNGKTSKKITIADCGQLE

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3D Structure

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PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

L-Proline

Drug Info

Approved

Malnutrition

[2], [3]

Mode of Action

[+] 2 Modes of Action

Binder

[+] 1 Binder drugs

L-Proline

Drug Info

[1]

Inhibitor

[+] 6 Inhibitor drugs

(3r)-1-Acetyl-3-Methylpiperidine

Drug Info

[4]

1-(3-benzyloxy-pyridin-2-yl)-3-phenyl-urea

Drug Info

[5]

3-[3-(3-benzyloxy-pyridin-2-yl)-ureido]-benzamide

Drug Info

[5]

4-[3-(3-benzyloxy-pyridin-2-yl)-ureido]-benzamide

Drug Info

[5]

7-AMINO-4-METHYL-CHROMEN-2-ONE

Drug Info

[6]

Ethyl Oxo(Piperidin-1-Yl)Acetate

Drug Info

[6]

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: Amifampridine

Ligand Info

Structure Description

Structure of cyclophilin A in complex with pyridine-3,4-diamine

PDB:5NOW

Method

X-ray diffraction

Resolution

1.48 Å

Mutation

[7]

PDB Sequence

MVNPTVFFDI

¹⁰

AVDGEPLGRV

²⁰

SFELFADKVP

³⁰

KTAENFRALS

⁴⁰

TGEKGFGYKG

⁵⁰

SCFHRIIPGF

⁶⁰

MCQGGDFTRH

⁷⁰

NGTGGKSIYG

⁸⁰

EKFEDENFIL

⁹⁰

KHTGPGILSM

¹⁰⁰

ANAGPNTNGS

¹¹⁰

QFFICTAKTE

¹²⁰

WLDGKHVVFG

¹³⁰

KVKEGMNIVE

¹⁴⁰

AMERFGSRNG

¹⁵⁰

KTSKKITIAD

¹⁶⁰

CGQLE

Residue

Distance (Å)

GLN63

4.850

GLY72

3.303

THR73

4.420

GLY74

3.877

LYS82

3.971

ALA101

3.829

ASN102

3.476

Residue

Distance (Å)

ALA103

4.117

THR107

3.190

ASN108

4.235

GLY109

3.576

SER110

4.857

GLN111

3.623

Ligand Name: L-alanine

Ligand Info

Structure Description

CYCLOPHILIN A COMPLEXED WITH DIPEPTIDE ALA-PRO

PDB:2CYH

Method

X-ray diffraction

Resolution

1.64 Å

Mutation

[8]

PDB Sequence

VNPTVFFDIA

¹¹

VDGEPLGRVS

²¹

FELFADKVPK

³¹

TAENFRALST

⁴¹

GEKGFGYKGS

⁵¹

CFHRIIPGFM

⁶¹

CQGGDFTRHN

⁷¹

GTGGKSIYGE

⁸¹

KFEDENFILK

⁹¹

HTGPGILSMA

¹⁰¹

NAGPNTNGSQ

¹¹¹

FFICTAKTEW

¹²¹

LDGKHVVFGK

¹³¹

VKEGMNIVEA

¹⁴¹

MERFGSRNGK

¹⁵¹

TSKKITIADC

¹⁶¹

GQLE

Residue

Distance (Å)

ARG55

4.921

GLN63

3.175

ALA101

3.314

Residue

Distance (Å)

ASN102

1.887

ALA103

4.069

HIS126

3.357

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

There is no similarity protein (E value < 0.005) for this target


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
Viral life cycle - HIV-1	hsa03250	Affiliated Target
Class: Genetic Information Processing => Information processing in viruses	Pathway Hierarchy
Necroptosis	hsa04217	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy

Degree	6	Degree centrality	6.45E-04	Betweenness centrality	2.15E-04
Closeness centrality	2.07E-01	Radiality	1.36E+01	Clustering coefficient	1.33E-01
Neighborhood connectivity	1.53E+01	Topological coefficient	1.88E-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 Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
Reactome	[+] 11 Reactome Pathways	+
1	Platelet degranulation
2	Uncoating of the HIV Virion
3	Budding and maturation of HIV virion
4	Integration of provirus
5	Early Phase of HIV Life Cycle
6	Minus-strand DNA synthesis
7	Plus-strand DNA synthesis
8	Binding and entry of HIV virion
9	Assembly Of The HIV Virion
10	APOBEC3G mediated resistance to HIV-1 infection
11	Basigin interactions
WikiPathways	[+] 5 WikiPathways	+
1	Signaling by the B Cell Receptor (BCR)
2	Host Interactions of HIV factors
3	HIV Life Cycle
4	JAK/STAT
5	Cell surface interactions at the vascular wall

References

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REF 1

Mechanistic insight into the role of transition-state stabilization in cyclophilin A. J Am Chem Soc. 2009 Jan 14;131(1):147-52.

REF 2

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: 3314).

REF 3

Escherichia coli cyclophilin B binds a highly distorted form of trans-prolyl peptide isomer. Eur J Biochem. 2004 Sep;271(18):3794-803.

REF 4

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 5

Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A. J Med Chem. 2006 Feb 9;49(3):900-10.

REF 6

The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.

REF 7

Pushing the Limits of Detection of Weak Binding Using Fragment-Based Drug Discovery: Identification of New Cyclophilin Binders. J Mol Biol. 2017 Aug 4;429(16):2556-2570.

REF 8

Mechanistic implication of crystal structures of the cyclophilin-dipeptide complexes. Biochemistry. 1996 Jun 11;35(23):7362-8.

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