Target Information
| Target General Information | Top | |||||
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| Target ID |
T46245
(Former ID: TTDI02156)
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| Target Name |
Glutaminyl cyclase (QPCT)
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| Synonyms |
sQC; QPCT; QC; Glutamyl cyclase; GlutaminyltRNA cyclotransferase; Glutaminylpeptide cyclotransferase; EC
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| Gene Name |
QPCT
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Dementia [ICD-11: 6D80-6D8Z] | |||||
| Function |
Responsible for the biosynthesis of pyroglutamyl peptides. Has a bias against acidic and tryptophan residues adjacent to the N-terminal glutaminyl residue and a lack of importance of chain length after the second residue. Also catalyzes N-terminal pyroglutamate formation. In vitro, catalyzes pyroglutamate formation of N-terminally truncated form of APP amyloid-beta peptides [Glu-3]-beta-amyloid. May be involved in the N-terminal pyroglutamate formation of several amyloid-related plaque-forming peptides.
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| BioChemical Class |
Acyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.3.2.5
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| Sequence |
MAGGRHRRVVGTLHLLLLVAALPWASRGVSPSASAWPEEKNYHQPAILNSSALRQIAEGT
SISEMWQNDLQPLLIERYPGSPGSYAARQHIMQRIQRLQADWVLEIDTFLSQTPYGYRSF SNIISTLNPTAKRHLVLACHYDSKYFSHWNNRVFVGATDSAVPCAMMLELARALDKKLLS LKTVSDSKPDLSLQLIFFDGEEAFLHWSPQDSLYGSRHLAAKMASTPHPPGARGTSQLHG MDLLVLLDLIGAPNPTFPNFFPNSARWFERLQAIEHELHELGLLKDHSLEGRYFQNYSYG GVIQDDHIPFLRRGVPVLHLIPSPFPEVWHTMDDNEENLDESTIDNLNKILQVFVLEYLH L Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PQ-912 | Drug Info | Phase 2 | Dementia | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | PQ-912 | Drug Info | [1] | |||
| 2 | PBD150 | 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: L-tyrosine | Ligand Info | |||||
| Structure Description | Crystal structure of human glutaminyl cyclase in complex with neurotensin 1-5 | PDB:6YJY | ||||
| Method | X-ray diffraction | Resolution | 1.67 Å | Mutation | No | [4] |
| PDB Sequence |
GPAWPEEKNY
42 HQPAILNSSA52 LRQIAEGTSI62 SEMWQNDLQP72 LLIERYPGSP82 GSYAARQHIM 92 QRIQRLQADW102 VLEIDTFLSQ112 TPYGYRSFSN122 IISTLNPTAK132 RHLVLACHYD 142 SKYFSHWNNR152 VFVGATDSAV162 PCAMMLELAR172 ALDKKLLSLK182 TVSDSKPDLS 192 LQLIFFDGEE202 AFLHWSPQDS212 LYGSRHLAAK222 MASTPHPPGA232 RGTSQLHGMD 242 LLVLLDLIGA252 PNPTFPNFFP262 NSARWFERLQ272 AIEHELHELG282 LLKDHSLEGR 292 YFQNYSYGGV302 IQDDHIPFLR312 RGVPVLHLIP322 SPFPEVWHTM332 DDNEENLDES 342 TIDNLNKILQ352 VFVLEYLHL
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| Ligand Name: L-phenylalanine | Ligand Info | |||||
| Structure Description | Crystal structure of human glutaminyl cyclase in complex with Glu(gamma-hydrazide)-Phe-Ala | PDB:6YI1 | ||||
| Method | X-ray diffraction | Resolution | 1.92 Å | Mutation | No | [4] |
| PDB Sequence |
GPAWPEEKNY
42 HQPAILNSSA52 LRQIAEGTSI62 SEMWQNDLQP72 LLIERYPGSP82 GSYAARQHIM 92 QRIQRLQADW102 VLEIDTFLSQ112 TPYGYRSFSN122 IISTLNPTAK132 RHLVLACHYD 142 SKYFSHWNNR152 VFVGATDSAV162 PCAMMLELAR172 ALDKKLLSLK182 TVSDSKPDLS 192 LQLIFFDGEE202 AFLHWSPQDS212 LYGSRHLAAK222 MASTPHPPGA232 RGTSQLHGMD 242 LLVLLDLIGA252 PNPTFPNFFP262 NSARWFERLQ272 AIEHELHELG282 LLKDHSLEGR 292 YFQNYSYGGV302 IQDDHIPFLR312 RGVPVLHLIP322 SPFPEVWHTM332 DDNEENLDES 342 TIDNLNKILQ352 VFVLEYLHL
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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 Similarity Proteins
Human Tissue Distribution
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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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| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 1 NetPath Pathways | + | ||||
| 1 | TGF_beta_Receptor Signaling Pathway | |||||
| References | Top | |||||
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| REF 1 | Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer s Disease ImmunotherapyRoxanna Perez-Garmendia, Goar Gevorkian. Curr Neuropharmacol. 2013 September; 11(5): 491-498. | |||||
| REF 2 | ClinicalTrials.gov (NCT02389413) Safety and Tolerability of PQ912 in Subjects With Early Alzheimer's Disease. U.S. National Institutes of Health. | |||||
| REF 3 | The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship. J Med Chem. 2006 Jan 26;49(2):664-77. | |||||
| REF 4 | Hydrazides Are Potent Transition-State Analogues for Glutaminyl Cyclase Implicated in the Pathogenesis of Alzheimer's Disease. Biochemistry. 2020 Jul 21;59(28):2585-2591. | |||||
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