Target Information
Target General Information | Top | |||||
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Target ID |
T59056
(Former ID: TTDNC00572)
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Target Name |
Aldosterone synthase (CYP11B2)
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Synonyms |
Steroid 18hydroxylase; Cytochrome P450C18; Cytochrome P450Aldo; Cytochrome P450 11B2, mitochondrial; CYPXIB2; CYP11B2; Aldosteronesynthesizing enzyme; ALDOS
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Gene Name |
CYP11B2
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Hypertension [ICD-11: BA00-BA04] | |||||
Function |
Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone.
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BioChemical Class |
Paired donor oxygen oxidoreductase
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UniProt ID | ||||||
EC Number |
EC 1.14.15.4
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Sequence |
MALRAKAEVCVAAPWLSLQRARALGTRAARAPRTVLPFEAMPQHPGNRWLRLLQIWREQG
YEHLHLEMHQTFQELGPIFRYNLGGPRMVCVMLPEDVEKLQQVDSLHPCRMILEPWVAYR QHRGHKCGVFLLNGPEWRFNRLRLNPDVLSPKAVQRFLPMVDAVARDFSQALKKKVLQNA RGSLTLDVQPSIFHYTIEASNLALFGERLGLVGHSPSSASLNFLHALEVMFKSTVQLMFM PRSLSRWISPKVWKEHFEAWDCIFQYGDNCIQKIYQELAFNRPQHYTGIVAELLLKAELS LEAIKANSMELTAGSVDTTAFPLLMTLFELARNPDVQQILRQESLAAAASISEHPQKATT ELPLLRAALKETLRLYPVGLFLERVVSSDLVLQNYHIPAGTLVQVFLYSLGRNAALFPRP ERYNPQRWLDIRGSGRNFHHVPFGFGMRQCLGRRLAEAEMLLLLHHVLKHFLVETLTQED IKMVYSFILRPGTSPLLTFRAIN Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
HIT2.0 ID | T18LPB |
Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | Baxdrostat | Drug Info | Phase 2 | Hypertension | [2] | |
2 | MLS-101 | Drug Info | Phase 2 | Hypertension | [3] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 2 Inhibitor drugs | + | ||||
1 | Baxdrostat | Drug Info | [4] | |||
2 | MLS-101 | Drug Info | [3] |
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: Osilodrostat | Ligand Info | |||||
Structure Description | Human CYP11B2 in complex with LCI699 | PDB:7M8V | ||||
Method | X-ray diffraction | Resolution | 3.08 Å | Mutation | No | [5] |
PDB Sequence |
PRTVLPFEAM
41 PQHPGNRWLR51 LLQIWREQGY61 EHLHLEMHQT71 FQELGPIFRY81 NLRMVCVMLP 94 EDVEKLQQVD104 SLHPCRMILE114 PWVAYRQHRG124 HKCGVFLLNG134 PEWRFNRLRL 144 NPDVLSPKAV154 QRFLPMVDAV164 ARDFSQALKK174 KVLQNARGSL184 TLDVQPSIFH 194 YTIEASNLAL204 FGERLGLVGH214 SPSSASLNFL224 HALEVMFKST234 VQLMFMPRSL 244 SRWISPKVWK254 EHFEAWDCIF264 QYGDNCIQKI274 YQELAFNRPQ284 HYTGIVAELL 294 LKAELSLEAI304 KANSMELTAG314 SVDTTAFPLL324 MTLFELARNP334 DVQQILRQES 344 LAAAASISEH354 PQKATTELPL364 LRAALKETLR374 LYPVGLFLER384 VVSSDLVLQN 394 YHIPAGTLVQ404 VFLYSLGRNA414 ALFPRPERYN424 PQRWLDIRNF438 HHVPFGFGMR 448 QCLGRRLAEA458 EMLLLLHHVL468 KHFLVETLTQ478 EDIKMVYSFI488 LRPGTSPLLT 498 FRAI
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Ligand Name: Deoxycorticosterone | Ligand Info | |||||
Structure Description | Structure of human aldosterone synthase, CYP11B2, in complex with deoxycorticosterone | PDB:4DVQ | ||||
Method | X-ray diffraction | Resolution | 2.49 Å | Mutation | No | [6] |
PDB Sequence |
TVLPFEAMPQ
43 HPGNRWLRLL53 QIWREQGYEH63 LHLEMHQTFQ73 ELGPIFRYNL83 GGPRMVCVML 93 PEDVEKLQQV103 DSLHPCRMIL113 EPWVAYRQHR123 GHKCGVFLLN133 GPEWRFNRLR 143 LNPDVLSPKA153 VQRFLPMVDA163 VARDFSQALK173 KKVLQNARGS183 LTLDVQPSIF 193 HYTIEASNLA203 LFGERLGLVG213 HSPSSASLNF223 LHALEVMFKS233 TVQLMFMPRS 243 LSRWISPKVW253 KEHFEAWDCI263 FQYGDNCIQK273 IYQELAFNRP283 QHYTGIVAEL 293 LLKAELSLEA303 IKANSMELTA313 GSVDTTAFPL323 LMTLFELARN333 PDVQQILRQE 343 SLAAAASISE353 HPQKATTELP363 LLRAALKETL373 RLYPVGLFLE383 RVVSSDLVLQ 393 NYHIPAGTLV403 QVFLYSLGRN413 AALFPRPERY423 NPQRWLDIFH439 HVPFGFGMRQ 449 CLGRRLAEAE459 MLLLLHHVLK469 HFLVETLTQE479 DIKMVYSFIL489 RPGTSPLLTF 499 RAI
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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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Steroid hormone biosynthesis | hsa00140 | Affiliated Target |
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Class: Metabolism => Lipid metabolism | Pathway Hierarchy | ||
Aldosterone synthesis and secretion | hsa04925 | Affiliated Target |
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Class: Organismal Systems => Endocrine system | Pathway Hierarchy |
Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 6.98E-05 |
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Closeness centrality | 1.46E-01 | Radiality | 1.18E+01 | Clustering coefficient | 5.24E-01 |
Neighborhood connectivity | 1.03E+01 | Topological coefficient | 4.47E-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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Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Affiliated Biological Pathways | Top | |||||
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BioCyc | [+] 2 BioCyc Pathways | + | ||||
1 | Superpathway of steroid hormone biosynthesis | |||||
2 | Mineralocorticoid biosynthesis | |||||
KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
1 | Steroid hormone biosynthesis | |||||
2 | Metabolic pathways | |||||
Pathwhiz Pathway | [+] 1 Pathwhiz Pathways | + | ||||
1 | Steroidogenesis | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Glucocorticoid biosynthesis | |||||
2 | Endogenous sterols | |||||
WikiPathways | [+] 5 WikiPathways | + | ||||
1 | Metapathway biotransformation | |||||
2 | ACE Inhibitor Pathway | |||||
3 | Oxidation by Cytochrome P450 | |||||
4 | Metabolism of steroid hormones and vitamin D | |||||
5 | Glucocorticoid & Mineralcorticoid Metabolism |
References | Top | |||||
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REF 1 | Medical management of Cushing's disease: what is the future . Pituitary. 2012 September; 15(3): 330-341. | |||||
REF 2 | Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023 Feb 2;388(5):395-405. | |||||
REF 3 | ClinicalTrials.gov (NCT05001945) A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Multicenter Phase 2 Study to Evaluate the Safety, Efficacy, and Tolerability of MLS-101 in Subjects With Uncontrolled Hypertension. U.S.National Institutes of Health. | |||||
REF 4 | Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. 2023 Feb 2;388(5):395-405. | |||||
REF 5 | Aldosterone Synthase Structure With Cushing Disease Drug LCI699 Highlights Avenues for Selective CYP11B Drug Design. Hypertension. 2021 Sep;78(3):751-759. | |||||
REF 6 | Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol Endocrinol. 2013 Feb;27(2):315-24. |
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