Target Information
| Target General Information | Top | |||||
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| Target ID |
T41750
(Former ID: TTDI02342)
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| Target Name |
Gastric inhibitory polypeptide receptor (GIPR)
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| Synonyms |
Glucosedependent insulinotropic polypeptide receptor; GIPR
Click to Show/Hide
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| Gene Name |
GIPR
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
| Function |
This is a receptor for GIP. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase.
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| BioChemical Class |
GPCR secretin
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| UniProt ID | ||||||
| Sequence |
MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLA
CNGSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHTQCEN PEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSF MLRAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVY LHSLLVLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIR TPILMTILINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPV TEEQARGALRFAKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQ RQLPERAFRALPSGSGPGEVPTSRGLSSGTLPGPGNEASRELESYC Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Tirzepatide | Drug Info | Approved | Type 2 diabetes | [2] | |
| Clinical Trial Drug(s) | [+] 8 Clinical Trial Drugs | + | ||||
| 1 | Retatrutide | Drug Info | Phase 3 | Obesity | [3] | |
| 2 | AMG 133 | Drug Info | Phase 2 | Obesity | [4] | |
| 3 | LY3437943 | Drug Info | Phase 2 | Obesity | [5] | |
| 4 | CT 868 | Drug Info | Phase 1 | Type 2 diabetes | [6] | |
| 5 | CT-388 | Drug Info | Phase 1 | Obesity | [7] | |
| 6 | LY3532226 | Drug Info | Phase 1 | Type 2 diabetes | [8] | |
| 7 | LY3537021 | Drug Info | Phase 1 | Type 2 diabetes | [9] | |
| 8 | SAR438335 | Drug Info | Phase 1 | Type-2 diabetes | [1] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | RG7685 | Drug Info | Discontinued in Phase 2 | Type-2 diabetes | [10] | |
| 2 | RG7697 | Drug Info | Discontinued in Phase 2 | Type-2 diabetes | [11] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Agonist | [+] 6 Agonist drugs | + | ||||
| 1 | Tirzepatide | Drug Info | [12] | |||
| 2 | Retatrutide | Drug Info | [13] | |||
| 3 | LY3437943 | Drug Info | [15] | |||
| 4 | LY3532226 | Drug Info | [18] | |||
| 5 | LY3537021 | Drug Info | [9] | |||
| 6 | SAR438335 | Drug Info | [1] | |||
| Antagonist/GLP1 agonist | [+] 1 Antagonist/GLP1 agonist drugs | + | ||||
| 1 | AMG 133 | Drug Info | [14] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | CT 868 | Drug Info | [16] | |||
| 2 | CT-388 | Drug Info | [17] | |||
| 3 | RG7685 | Drug Info | [19] | |||
| 4 | RG7697 | Drug Info | [20] | |||
| 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-glutamic acid | Ligand Info | |||||
| Structure Description | Cryo-EM structure of the GIPR/GLP-1R/GCGR triagonist peptide 20-bound human GIPR-Gs complex | PDB:7FIN | ||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | Yes | [21] |
| PDB Sequence |
QTAGELYQRW
39 ERYRRECQET49 LAAAACNGSF65 DMYVCWDYAA75 PNATARASCP85 WYLPWHHHVA 95 AGFVLRQCGS105 DGQWGLWRDH115 TQCENPEKNE125 AFLDQRLILE135 RLQVMYTVGY 145 SLSLATLLLA155 LLILSLFRRL165 HCTRNYIHIN175 LFTSFMLRAA185 AILSRDRLLP 195 RPGPYLGDQA205 LALWNQALAA215 CRTAQIVTQY225 CVGANYTWLL235 VEGVYLHSLL 245 VLVGGSEEGH255 FRYYLLLGWG265 APALFVIPWV275 IVRYLYENTQ285 CWERNEVKAI 295 WWIIRTPILM305 TILINFLIFI315 RILGILLSKL325 RTRQMRCRDY335 RLRLARSTLF 345 LVPLLGVHEV355 VFAPVTEEQA365 RGALRFAKLG375 FEIFLSSFQG385 FLVSVLYCFI 395 NKEVQSEIRR405 GWHHCRLRRS415
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| Ligand Name: Alpha-Aminoisobutyric Acid | Ligand Info | |||||
| Structure Description | cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to tirzepatide | PDB:7RBT | ||||
| Method | Electron microscopy | Resolution | 3.08 Å | Mutation | No | [22] |
| PDB Sequence |
GQTAGELYQR
38 WERYRRECQE48 TLAAAEPPSG58 LACNGSFDMY68 VCWDYAAPNA78 TARASCPWYL 88 PWHHHVAAGF98 VLRQCGSDGQ108 WGLWRDHTQC118 ENPEKNEAFL128 DQRLILERLQ 138 VMYTVGYSLS148 LATLLLALLI158 LSLFRRLHCT168 RNYIHINLFT178 SFMLRAAAIL 188 SRDRLLPRPG198 PYLGDQALAL208 WNQALAACRT218 AQIVTQYCVG228 ANYTWLLVEG 238 VYLHSLLVLV248 GGSEEGHFRY258 YLLLGWGAPA268 LFVIPWVIVR278 YLYENTQCWE 288 RNEVKAIWWI298 IRTPILMTIL308 INFLIFIRIL318 GILLSKLRTR328 DYRLRLARST 343 LTLVPLLGVH353 EVVFAPVTEE363 QARGALRFAK373 LGFEIFLSSF383 QGFLVSVLYC 393 FINKEVQSEI403 RRGWHHCR
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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 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 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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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| cAMP signaling pathway | hsa04024 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 1.78E-06 |
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| Closeness centrality | 1.77E-01 | Radiality | 1.29E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+01 | Topological coefficient | 6.00E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 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 | cAMP signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | G alpha (s) signalling events | |||||
| 2 | Glucagon-type ligand receptors | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | GPCRs, Class B Secretin-like | |||||
| 2 | GPCR ligand binding | |||||
| 3 | GPCR downstream signaling | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215866. | |||||
| REF 3 | ClinicalTrials.gov (NCT05882045) A Randomized, Double-Blind, Phase 3 Study to Investigate the Efficacy and Safety of LY3437943 Once Weekly Compared to Placebo in Participants With Severe Obesity and Established Cardiovascular Disease. U.S.National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT05669599) A Phase 2 Randomized, Placebo-controlled, Double-blind, Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of AMG 133 in Adult Subjects With Overweight or Obesity, With or Without Type 2 Diabetes Mellitus. U.S.National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT04881760) A Phase 2 Study of Once-Weekly LY3437943 Compared With Placebo in Participants Who Have Obesity or Are Overweight With Weight-Related Comorbidities. U.S.National Institutes of Health. | |||||
| REF 6 | Clinical pipeline report, company report or official report of Carmot Therapeutics. | |||||
| REF 7 | ClinicalTrials.gov (NCT04838405) A Phase 1 Randomized, Double Blind, Placebo Controlled, Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CT-388 in Otherwise Healthy Overweight and Obese Adult Participants and in Obese Patients With Type 2 Diabetes Mellitus. U.S.National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT05407961) A Phase 1b, 2-Part, Investigator- and Participant-Blind, Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LY3532226 in Participants With Type 2 Diabetes Mellitus. U.S.National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT04586907) A Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LY3537021 in Healthy Participants and Patients With Type 2 Diabetes Mellitus. U.S.National Institutes of Health. | |||||
| REF 10 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031660) | |||||
| REF 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034341) | |||||
| REF 12 | Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes. J Clin Endocrinol Metab. 2021 Jan 23;106(2):388-396. | |||||
| REF 13 | Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin Investig Drugs. 2023 May;32(5):355-359. | |||||
| REF 14 | An update on peptide-based therapies for type 2 diabetes and obesity. Peptides. 2023 Mar;161:170939. | |||||
| REF 15 | LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022 Sep 6;34(9):1234-1247.e9. | |||||
| REF 16 | Clinical pipeline report, company report or official report of Carmot Therapeutics. | |||||
| REF 17 | Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs. 2021 Sep;26(3):231-243. | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight | |||||
| REF 19 | Company report (Roche pipeline: October 16, 2012) | |||||
| REF 20 | Company report (Roche pipeline: 16 October 2014) | |||||
| REF 21 | Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun. 2022 Feb 25;13(1):1057. | |||||
| REF 22 | Structural determinants of dual incretin receptor agonism by tirzepatide. Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2116506119. | |||||
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