Target Information
| Target General Information | Top | |||||
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| Target ID |
T27889
(Former ID: TTDNC00602)
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| Target Name |
Angiotensin-converting enzyme 2 (ACE2)
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| Synonyms |
Processed angiotensinconverting enzyme 2; Metalloprotease MPROT15; Angiotensinconverting enzyme homolog; Angiotensinconverting enzyme 2; ACErelated carboxypeptidase; ACEH; ACE2
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| Gene Name |
ACE2
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Intrathoracic organs injury [ICD-11: NB32] | |||||
| 2 | Acute diabete complication [ICD-11: 5A2Y] | |||||
| 3 | Pulmonary hypertension [ICD-11: BB01] | |||||
| Function |
Carboxypeptidase which converts angiotensin I to angiotensin 1-9, a peptide of unknown function, and angiotensin II to angiotensin 1-7, a vasodilator. Also able to hydrolyze apelin- 13 and dynorphin-13 with high efficiency. May be an important regulator of heart function. In case of human coronaviruses SARS and HCoV-NL63 infections, serve as functional receptor for the spike glycoprotein of both coronaviruses.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.17.23
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| Sequence |
MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITEENVQ
NMNNAGDKWSAFLKEQSTLAQMYPLQEIQNLTVKLQLQALQQNGSSVLSEDKSKRLNTIL NTMSTIYSTGKVCNPDNPQECLLLEPGLNEIMANSLDYNERLWAWESWRSEVGKQLRPLY EEYVVLKNEMARANHYEDYGDYWRGDYEVNGVDGYDYSRGQLIEDVEHTFEEIKPLYEHL HAYVRAKLMNAYPSYISPIGCLPAHLLGDMWGRFWTNLYSLTVPFGQKPNIDVTDAMVDQ AWDAQRIFKEAEKFFVSVGLPNMTQGFWENSMLTDPGNVQKAVCHPTAWDLGKGDFRILM CTKVTMDDFLTAHHEMGHIQYDMAYAAQPFLLRNGANEGFHEAVGEIMSLSAATPKHLKS IGLLSPDFQEDNETEINFLLKQALTIVGTLPFTYMLEKWRWMVFKGEIPKDQWMKKWWEM KREIVGVVEPVPHDETYCDPASLFHVSNDYSFIRYYTRTLYQFQFQEALCQAAKHEGPLH KCDISNSTEAGQKLFNMLRLGKSEPWTLALENVVGAKNMNVRPLLNYFEPLFTWLKDQNK NSFVGWSTDWSPYADQSIKVRISLKSALGDKAYEWNDNEMYLFRSSVAYAMRQYFLKVKN QMILFGEEDVRVANLKPRISFNFFVTAPKNVSDIIPRTEVEKAIRMSRSRINDAFRLNDN SLEFLGIQPTLGPPNQPPVSIWLIVFGVVMGVIVVGIVILIFTGIRDRKKKNKARSGENP YASIDISKGENNPGFQNTDDVQTSF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A03584 | |||||
| HIT2.0 ID | T70B7U | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
| 1 | GSK2586881 | Drug Info | Phase 2 | Acute lung injury | [2] | |
| 2 | ORE-1001 | Drug Info | Phase 1/2 | Diabetic complication | [3] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Modulator | [+] 1 Modulator drugs | + | ||||
| 1 | GSK2586881 | Drug Info | [1] | |||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | ORE-1001 | Drug Info | [4] | |||
| 2 | PMID18324760C28 | Drug Info | [5] | |||
| Activator | [+] 1 Activator drugs | + | ||||
| 1 | XNT | Drug Info | [6] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: ORE-1001 | Ligand Info | |||||
| Structure Description | Inhibitor Bound Human Angiotensin Converting Enzyme-Related Carboxypeptidase (ACE2) | PDB:1R4L | ||||
| Method | X-ray diffraction | Resolution | 3.00 Å | Mutation | No | [7] |
| PDB Sequence |
STIEEQAKTF
28 LDKFNHEAED38 LFYQSSLASW48 NYNTNITEEN58 VQNMNNAGDK68 WSAFLKEQST 78 LAQMYPLQEI88 QNLTVKLQLQ98 ALQQNGSSVL108 SEDKSKRLNT118 ILNTMSTIYS 128 TGKVCNPDNP138 QECLLLEPGL148 NEIMANSLDY158 NERLWAWESW168 RSEVGKQLRP 178 LYEEYVVLKN188 EMARANHYED198 YGDYWRGDYE208 VNGVDGYDYS218 RGQLIEDVEH 228 TFEEIKPLYE238 HLHAYVRAKL248 MNAYPSYISP258 IGCLPAHLLG268 DMWGRFWTNL 278 YSLTVPFGQK288 PNIDVTDAMV298 DQAWDAQRIF308 KEAEKFFVSV318 GLPNMTQGFW 328 ENSMLTDPGN338 VQKAVCHPTA348 WDLGKGDFRI358 LMCTKVTMDD368 FLTAHHEMGH 378 IQYDMAYAAQ388 PFLLRNGANE398 GFHEAVGEIM408 SLSAATPKHL418 KSIGLLSPDF 428 QEDNETEINF438 LLKQALTIVG448 TLPFTYMLEK458 WRWMVFKGEI468 PKDQWMKKWW 478 EMKREIVGVV488 EPVPHDETYC498 DPASLFHVSN508 DYSFIRYYTR518 TLYQFQFQEA 528 LCQAAKHEGP538 LHKCDISNST548 EAGQKLFNML558 RLGKSEPWTL568 ALENVVGAKN 578 MNVRPLLNYF588 EPLFTWLKDQ598 NKNSFVGWST608 DWSPYAD
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GLU145
4.054
ASN149
3.895
ARG273
2.736
PHE274
4.535
CYS344
4.133
HIS345
2.664
PRO346
3.088
THR347
4.034
ALA348
4.946
MET360
3.717
CYS361
4.375
LYS363
4.288
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| Ligand Name: 2-(Acetylamino)-2-Deoxy-a-D-Glucopyranose | Ligand Info | |||||
| Structure Description | Crystal structure of spike protein receptor-binding domain from the 2002-2003 SARS coronavirus human strain complexed with human-civet chimeric receptor ACE2 | PDB:3D0G | ||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | No | [8] |
| PDB Sequence |
STTEELAKTF
28 LETFNYEAQE38 LSYQSSVASW48 NYNTNITEEN58 VQNMNNAGDK68 WSAFLKEQST 78 LAQMYPLQEI88 QNLTVKLQLQ98 ALQQNGSSVL108 SEDKSKRLNT118 ILNTMSTIYS 128 TGKVCNPDNP138 QECLLLEPGL148 NEIMANSLDY158 NERLWAWESW168 RSEVGKQLRP 178 LYEEYVVLKN188 EMARANHYED198 YGDYWRGDYE208 VNGVDGYDYS218 RGQLIEDVEH 228 TFEEIKPLYE238 HLHAYVRAKL248 MNAYPSYISP258 IGCLPAHLLG268 DMWGRFWTNL 278 YSLTVPFGQK288 PNIDVTDAMV298 DQAWDAQRIF308 KEAEKFFVSV318 GLPNMTQGFW 328 ENSMLTDPGN338 VQKAVCHPTA348 WDLGKGDFRI358 LMCTKVTMDD368 FLTAHHEMGH 378 IQYDMAYAAQ388 PFLLRNGANE398 GFHEAVGEIM408 SLSAATPKHL418 KSIGLLSPDF 428 QEDNETEINF438 LLKQALTIVG448 TLPFTYMLEK458 WRWMVFKGEI468 PKDQWMKKWW 478 EMKREIVGVV488 EPVPHDETYC498 DPASLFHVSN508 DYSFIRYYTR518 TLYQFQFQEA 528 LCQAAKHEGP538 LHKCDISNST548 EAGQKLFNML558 RLGKSEPWTL568 ALENVVGAKN 578 MNVRPLLNYF588 EPLFTWLKDQ598 NKNSFVGWST608 DWSPYAD
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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
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There is no similarity protein (E value < 0.005) for this target
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Renin-angiotensin system | hsa04614 | Affiliated Target |
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| Class: Organismal Systems => Endocrine system | Pathway Hierarchy | ||
| Protein digestion and absorption | hsa04974 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 2.35E-04 |
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| Closeness centrality | 1.95E-01 | Radiality | 1.33E+01 | Clustering coefficient | 2.00E-01 |
| Neighborhood connectivity | 8.00E+00 | Topological coefficient | 2.38E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | Renin-angiotensin system | |||||
| 2 | Protein digestion and absorption | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Metabolism of Angiotensinogen to Angiotensins | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | ACE Inhibitor Pathway | |||||
| 2 | Metabolism of Angiotensinogen to Angiotensins | |||||
| References | Top | |||||
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| REF 1 | New Developments in the Pharmacological Treatment of Hypertension: Dead-End or a Glimmer at the Horizon . Curr Hypertens Rep. 2015; 17(6): 42. | |||||
| REF 2 | ClinicalTrials.gov (NCT01597635) The Safety, Tolerability, PK and PD of GSK2586881 in Patients With Acute Lung Injury. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01039597) Safety and Activity of ORE1001 in Subjects With Ulcerative Colitis. U.S. National Institutes of Health. | |||||
| REF 4 | Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice. Inflamm Res. 2009 Nov;58(11):819-27. | |||||
| REF 5 | Development of potent and selective phosphinic peptide inhibitors of angiotensin-converting enzyme 2. J Med Chem. 2008 Apr 10;51(7):2216-26. | |||||
| REF 6 | Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008 May;51(5):1312-7. | |||||
| REF 7 | ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004 Apr 23;279(17):17996-8007. | |||||
| REF 8 | Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. J Virol. 2008 Jul;82(14):6984-91. | |||||
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