Target Information

Target General Information

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Target ID

T33966 (Former ID: TTDR01204)

Target Name

Carboxypeptidase A1 (CPA1)

Synonyms

CPA

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Gene Name

CPA1

Target Type

Literature-reported target

[1]

Function

Carboxypeptidase that catalyzes the release of a C-terminal amino acid, but has little or no action with -Asp, -Glu, -Arg, -Lys or -Pro.

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BioChemical Class

Peptidase

UniProt ID

CBPA1_HUMAN

EC Number

EC 3.4.17.1

Sequence

MRGLLVLSVLLGAVFGKEDFVGHQVLRISVADEAQVQKVKELEDLEHLQLDFWRGPAHPG
SPIDVRVPFPSIQAVKIFLESHGISYETMIEDVQSLLDEEQEQMFAFRSRARSTDTFNYA
TYHTLEEIYDFLDLLVAENPHLVSKIQIGNTYEGRPIYVLKFSTGGSKRPAIWIDTGIHS
REWVTQASGVWFAKKITQDYGQDAAFTAILDTLDIFLEIVTNPDGFAFTHSTNRMWRKTR
SHTAGSLCIGVDPNRNWDAGFGLSGASSNPCSETYHGKFANSEVEVKSIVDFVKDHGNIK
AFISIHSYSQLLMYPYGYKTEPVPDQDELDQLSKAAVTALASLYGTKFNYGSIIKAIYQA
SGSTIDWTYSQGIKYSFTFELRDTGRYGFLLPASQIIPTAKETWLALLTIMEHTLNHPY

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3D Structure

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PDB

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: (2R)-4-methyl-2-[(1S)-1-sulfanylethyl]pentanoic acid

Ligand Info

Structure Description

Crystal structure of the human CARBOXYPEPTIDASE A1 in complex with a thiirane mechanism-based inhibitor

PDB:5OM9

Method

X-ray diffraction

Resolution

1.80 Å

Mutation

[4]

PDB Sequence

KEDFVGHQVL

^-84

RISVADEAQV

^-74

QKVKELEDLE

^-64

HLQLDFWRGP

^-54

AHPGSPIDVR

^-44

VPFPSIQAVK

^-34

IFLESHGISY

^-24

ETMIEDVQSL

^-14

LDEEQEQMFR

STDTFNYATY

¹²

HTLEEIYDFL

²²

DLLVAENPHL

³²

VSKIQIGNTY

⁴²

EGRPIYVLKF

⁵²

STGGSKRPAI

⁶²

WIDTGIHSRE

⁷²

WVTQASGVWF

⁸²

AKKITQDYGQ

⁹²

DAAFTAILDT

¹⁰²

LDIFLEIVTN

¹¹²

PDGFAFTHST

¹²²

NRMWRKTRSH

¹³²

TAGSLCIGVD

¹⁴²

PNRNWDAGFG

¹⁵²

LSGASSNPCS

¹⁶²

ETYHGKFANS

¹⁷²

EVEVKSIVDF

¹⁸²

VKDHGNIKAF

¹⁹²

ISIHSYSQLL

²⁰²

MYPYGYKTEP

²¹²

VPDQDELDQL

²²²

SKAAVTALAS

²³²

LYGTKFNYGS

²⁴²

IIKAIYQASG

²⁵²

STIDWTYSQG

²⁶²

IKYSFTFELR

²⁷²

DTGRYGFLLP

²⁸²

ASQIIPTAKE

²⁹²

TWLALLTIME

³⁰²

HTLNHP

Residue

Distance (Å)

HIS69

3.441

GLU72

3.672

ARG127

3.421

ASN144

2.920

ARG145

2.824

HIS196

3.683

SER197

4.193

TYR198

4.074

Residue

Distance (Å)

MET203

3.822

ILE243

3.983

ILE247

4.140

TYR248

2.504

ALA250

3.690

SER253

4.340

THR268

3.575

GLU270

1.458

Ligand Name: Octane-1,3,5,7-Tetracarboxylic Acid

Ligand Info

Structure Description

Crystal Structure of Human Carboxypeptidase A1

PDB:2V77

Method

X-ray diffraction

Resolution

1.60 Å

Mutation

[5]

PDB Sequence

ARSTDTFNYA

¹⁰

TYHTLEEIYD

²⁰

FLDLLVAENP

³⁰

HLVSKIQIGN

⁴⁰

TYEGRPIYVL

⁵⁰

KFSTGGSKRP

⁶⁰

AIWIDTGIHS

⁷⁰

REWVTQASGV

⁸⁰

WFAKKITQDY

⁹⁰

GQDAAFTAIL

¹⁰⁰

DTLDIFLEIV

¹¹⁰

TNPDGFAFTH

¹²⁰

STNRMWRKTR

¹³⁰

SHTAGSLCIG

¹⁴⁰

VDPNRNWDAG

¹⁵⁰

FGLSGASSNP

¹⁶⁰

CSETYHGKFA

¹⁷⁰

NSEVEVKSIV

¹⁸⁰

DFVKDHGNIK

¹⁹⁰

AFISIHSYSQ

²⁰⁰

LLMYPYGYKT

²¹⁰

EPVPDQDELD

²²⁰

QLSKAAVTAL

²³⁰

ASLYGTKFNY

²⁴⁰

GSIIKAIYQA

²⁵⁰

SGSTIDWTYS

²⁶⁰

QGIKYSFTFE

²⁷⁰

LRDTGRYGFL

²⁸⁰

LPASQIIPTA

²⁹⁰

KETWLALLTI

³⁰⁰

MEHTLNHP

Residue

Distance (Å)

HIS69

2.967

ARG71

3.340

GLU72

3.148

ARG127

2.859

ASP142

4.764

ASN144

2.872

ARG145

2.760

HIS196

3.341

SER197

3.348

TYR198

3.216

Residue

Distance (Å)

SER199

4.192

MET203

3.620

ILE243

4.284

ILE247

3.764

TYR248

2.630

ALA250

4.749

THR268

2.587

PHE269

4.099

GLU270

2.695

PHE279

3.516

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
Pancreatic secretion	hsa04972	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy
Protein digestion and absorption	hsa04974	Affiliated Target
Class: Organismal Systems => Digestive system	Pathway Hierarchy

Degree	4	Degree centrality	4.30E-04	Betweenness centrality	1.39E-07
Closeness centrality	4.30E-04	Radiality	9.78E-03	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.00E+00	Topological coefficient	.	Eccentricity	1
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-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

A new type of five-membered heterocyclic inhibitors of basic metallocarboxypeptidases. Eur J Med Chem. 2009 Aug;44(8):3266-71.

REF 2

Thiol-based angiotensin-converting enzyme 2 inhibitors: P1 modifications for the exploration of the S1 subsite. Bioorg Med Chem Lett. 2008 Jan 15;18(2):732-7.

REF 3

Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis. J Med Chem. 2007 Nov 29;50(24):6095-103.

REF 4

Discovery of Mechanism-Based Inactivators for Human Pancreatic Carboxypeptidase A from a Focused Synthetic Library. ACS Med Chem Lett. 2017 Sep 22;8(10):1122-1127.

REF 5

Direct interaction between a human digestive protease and the mucoadhesive poly(acrylic acid). Acta Crystallogr D Biol Crystallogr. 2008 Jul;D64(Pt 7):784-91.

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