Target Information
| Target General Information | Top | |||||
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| Target ID |
T12075
(Former ID: TTDI02226)
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| Target Name |
Hedgehog protein (SHH)
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| Synonyms |
Sonic hedgehog protein C-product; Sonic hedgehog protein; SHH; HHG-1
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| Gene Name |
SHH
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Intercellular signal essential for a variety of patterning events duringdevelopment: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior- posterior axis of the developinglimb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction. Activates the transcription of target genes by interacting with its receptor PTCH1 to prevent normal inhibition by PTCH1 on the constitutive signaling activity of SMO.
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| BioChemical Class |
Hedgehog
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| UniProt ID | ||||||
| Sequence |
MLLLARCLLLVLVSSLLVCSGLACGPGRGFGKRRHPKKLTPLAYKQFIPNVAEKTLGASG
RYEGKISRNSERFKELTPNYNPDIIFKDEENTGADRLMTQRCKDKLNALAISVMNQWPGV KLRVTEGWDEDGHHSEESLHYEGRAVDITTSDRDRSKYGMLARLAVEAGFDWVYYESKAH IHCSVKAENSVAAKSGGCFPGSATVHLEQGGTKLVKDLSPGDRVLAADDQGRLLYSDFLT FLDRDDGAKKVFYVIETREPRERLLLTAAHLLFVAPHNDSATGEPEASSGSGPPSGGALG PRALFASRVRPGQRVYVVAERDGDRRLLPAAVHSVTLSEEAAGAYAPLTAQGTILINRVL ASCYAVIEEHSWAHRAFAPFRLAHALLAALAPARTDRGGDSGGGDRGGGGGRVALTAPGA ADAPGAGATAGIHWYSQLLYQIGTWLLDSEALHPLGMAVKSS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T35OPL | |||||
| 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: L-serine | Ligand Info | |||||
| Structure Description | Cryo-EM structure of human Ptch1 and ShhN complex | PDB:6DMY | ||||
| Method | Electron microscopy | Resolution | 3.60 Å | Mutation | No | [2] |
| PDB Sequence |
LTPLAYKQFI
48 PNVAEKTLGA58 SGRYEGKISR68 NSERFKELTP78 NYNPDIIFKD88 EENTGADRLM 98 TQRCKDKLNA108 LAISVMNQWP118 GVKLRVTEGW128 DEDGHHSEES138 LHYEGRAVDI 148 TTSDRDRSKY158 GMLARLAVEA168 GFDWVYYESK178 AHIHCSVKAE188 N |
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| Ligand Name: Cholesterol | Ligand Info | |||||
| Structure Description | Revised cryo-EM structure of the human 2:1 Ptch1-Shh complex | PDB:6RVD | ||||
| Method | Electron microscopy | Resolution | 3.50 Å | Mutation | No | [3] |
| PDB Sequence |
CGPGRGFGKR
33 RHPKKLTPLA43 YKQFIPNVAE53 KTLGASGRYE63 GKISRNSERF73 KELTPNYNPD 83 IIFKDEENTG93 ADRLMTQRCK103 DKLNALAISV113 MNQWPGVKLR123 VTEGWDEDGH 133 HSEESLHYEG143 RAVDITTSDR153 DRSKYGMLAR163 LAVEAGFDWV173 YYESKAHIHC 183 SVKAENSVAA193 KSGG
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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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| Hedgehog signaling pathway | hsa04340 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Axon guidance | hsa04360 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Degree | 15 | Degree centrality | 1.61E-03 | Betweenness centrality | 8.89E-04 |
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| Closeness centrality | 2.02E-01 | Radiality | 1.35E+01 | Clustering coefficient | 1.14E-01 |
| Neighborhood connectivity | 8.33E+00 | Topological coefficient | 1.16E-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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| References | Top | |||||
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| REF 1 | Sonic Hedgehog Protein is Frequently Up-Regulated in Pancreatic Cancer Compared to Colorectal Cancer. Pathol Oncol Res. 2018 Dec 11. | |||||
| REF 2 | Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science. 2018 Aug 10;361(6402):eaas8935. | |||||
| REF 3 | The morphogen Sonic hedgehog inhibits its receptor Patched by a pincer grasp mechanism. Nat Chem Biol. 2019 Oct;15(10):975-982. | |||||
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