Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery
Abstract
:1. Introduction
2. GPCRs Liganded by Lipid Mediators
2.1. A Brief Primer on GPCRs
2.2. Lipid GPCRs and Associated Drugs
3. Progress in Structural Biology of Lipid GPCRs
The First Lipid GPCR Structure
4. Structural and Functional Features of Lipid GPCRs
4.1. Organization of Extracellular Domains in Lipid GPCRs
4.2. Mode and Dynamics of Lipid Ligand Access
4.3. Canonical and Non-Canonical Ligand Binding in Lipid Receptors
4.4. Non-Canonical or Allosteric Sites
5. The Challenges and Future Perspectives on the Development of GPCR-Centric Therapeutics
5.1. Beyond Simple Agonism and Antagonism
5.2. Antibody-Based Therapeutics
5.3. Advances in Computational Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cognate Receptor Name; Gene Name and Uniprot ID | Protein Engineering/Modification | Methodology | Structures | |
---|---|---|---|---|
Prostanoids | Prostaglandin D2 receptor 2 (DP2) #; PTGDR2; Q9Y5Y4 | T4-lysozyme (mT4L) with 8-aa linker insert in ICL3. | X-ray crystallography (XRD) | Antagonists fevipiprant [6D26 Inactive; 2.80 Å], CAY10471 [6D27 Inactive; 2.74 Å] [31] |
T4-lysozyme (mT4L) with 8-aa linker insert in ICL3. | Serial femtosecond crystallography (SFX) with X-ray free electron laser (XFEL) | Agonist 15m-PGD2 [7M8W Inactive; 2.61 A] [32] | ||
Prostaglandin E2 receptor EP2 subtype; PTGER2; P43116 | No modifications. | Cryo-electron microscopy (cryo-EM) | Endogenous agonist PGE2 + G-protein Gs [7CX2 Active; 2.80 Å], synthetic agonists taprenepag + Gs [7CX3 Active; 2.80 Å], evatanepag (CP-533536) + Gs [7CX4 Active; 2.90 Å] [33] | |
Prostaglandin E2 receptor EP3 subtype; PTGER3; P43115 | Thermostabilized apocytochrome b562RIL (bRIL) insert in ICL3; N- and C-terminal truncation; four thermostabilizing mutations | Lipidic cubic phase crystallization (LCP); XRD | Agonist PGE2 [6AK3 Active; 2.90 Å] [34] | |
T4-lysozyme insertion in ICL3; C-terminal truncation. | LCP; XFEL | Agonist misoprostol [6M9T Active; 2.5 Å] [35] | ||
Prostaglandin E2 receptor EP4 subtype; PTGER4; P35408 | Stabilizing anti-human EP4 antibody (IgG#001); removal of N-glycosylation site; ICL3, N- and C-terminal truncation; two thermostabilizing point mutations | LCP; XRD | Antagonists ONO-9990614 [5YHL Inactive; 4.20 Å], ONO-AE3-208 [5YWY Inactive; 3.20 Å] [36]; | |
Gs-stabilizing nanobody Nb35 | Cryo-EM | Agonist PGE2 + Gs + nanobody Nb35 [7D7M Active; 3.30 Å] [37] | ||
Thromboxane A2 receptor; TBXA2R; P21731 | Thermostabilized b562RIL (bRIL) insert in N-terminal [6IIV]; rubredoxin insert in ICL3 [6IIV]; C-terminus truncation; one thermostabilizing point mutation | LCP; XRD | Antagonists ramatroban [6IIU Intermediate; 2.50 Å] dalotroban [6IIV Intermediate, 3.00 Å] [38] | |
Platelet-activating factor | Platelet-activating factor receptor; PTAFR; P25105 | Flavodoxin insert [5ZKP] and T4-lysozyme [5ZKQ] insert in ICL3; | LCP; XRD | Antagonists SR 27417 [5ZKP Other; 2.81 Å] and BT-491 [5ZKQ Intermediate; 2.90 Å] [39] |
Lysophospholipids | Sphingosine 1-phosphate receptor 1; S1PR1; P21453 | T4-lysozyme insert in ICL3 | XRD [3V2W]; microdiffraction [3V2Y] | Antagonist ML056 [3V2W Inactive, 3.35 Å; 3V2Y Inactive, 2.80 Å] [40] |
Sphingosine 1-phosphate receptor 3; S1PR3; Q99500 | C-terminus truncation; removal of N-glycosylation site; stabilizing Fab antibody fragment (Fab AS55) | LCP; XRD | Natural agonist d18:1 S1P + Fab AS55 [7C4S Active; 3.2 Å] [41] | |
Lysophosphatidic acid receptor 1; LPAR1; Q92633 | bRIL insert in ICL3; C-terminus truncation; engineered disulfide bridges [4Z36]; stabilizing antagonists | XRD | Selective antagonists ONO-9780307 [4Z34 Inactive; 3.0 Å], ONO-9910539 [4Z35 Inactive; 2.90 Å], ONO-3080573 [4Z36 Inactive; 2.90 Å] [42] | |
Lysophosphatidic acid receptor 6; drlpar6a; Q08BG4 | T4-lysozyme insert in ICL3 | LCP; XRD | Apo state [5XSZ Intermediate; 3.20 Å] [43] | |
Leukotrienes | Leukotriene B4 receptor 1; cpLTB4R; Q9WTK1 | T4-lysozyme insert in ICL3; N-terminus truncation; thermostabilizing point mutations | LCP; XRD | Antagonist BIIL260 [5X33 Inactive; 3.70 Å] [44] |
Leukotriene B4 receptor 1; LTB4R; Q15722 | Flavodoxin insert in ICL3; N- and C-termini truncation; thermostabilizing point mutations | LCP; XRD | Antagonist ML-D-046 [7K15 Inactive; 2.88 Å] [45] | |
Cysteinyl leukotriene receptor 1; CYSLTR1; Q9Y271 | Thermostabilized b562RIL (bRIL) insert in ICL3; C-terminal truncation. | LCP; SFX with XFEL | Antagonists pranlukast [6RZ4 Intermediate; 2.70 Å] and zafirlukast [6RZ5 Intermediate; 2.53 Å] [46] | |
Cysteinyl leukotriene receptor 2; CYSLTR2; Q9NS75 | Thermostabilized b562RIL (bRIL) insert in ICL3; stabilizing mutations; N- and C-termini truncation | LCP; XRD | Antagonists ONO-2570366 [6RZ6 Intermediate, 6RZ7 Intermediate; 2.43 Å], ONO-2080365 [6RZ8 Intermediate; 2.70 Å], and ONO-2770372 [6RZ9 Intermediate; 2.73 Å] [47] | |
Free fatty acids | Free fatty acid receptor 1 (GRP40); O14842; FFAR1 | T4-lysozyme insert in ICL3 | LCP; XRD | Allosteric partial agonist TAK-875 [4PHU Intermediate; 2.30 Å] [48] |
T4-lysozyme insert in ICL3; three thermostabilizing mutations; | LCP; XRD | AgoPAM AP8 and partial agonist MK-8666 [5TZY Inactive; 3.22 Å], MK-8666 [5TZR Intermediate; 2.20 Å] [49]; | ||
T4-lysozyme insert in ICL3 | LCP; XRD | Full agonist “compound 1” [5KW2 Intermediate; 2.76 Å] [50] | ||
Cannabinoids | Cannabinoid receptor 1 (CB1); CNR1; P21554 | Flavodoxin insert in ICL3; stabilizing antagonist; N- and C-termini truncation; four thermostabilizing mutations | LCP; XRD | Antagonist AM6538 [5TGZ Inactive; 2.80 Å] [51] |
Thermostable P. abyssi glycogen synthase (PGS) domain insert in ICL3; N- and C-termini truncation; one thermostabilizing mutation | LCP; XRD | Inverse agonist taranabant [5U09 Inactive; 2.6 Å] [52] | ||
Flavodoxin insert in ICL3; N- and C-termini truncation; four thermostabilizing mutations; stabilizing agonists | LCP; XRD | Agonists AM11542 [5XRA Active; 2.80 Å], AM841 [5XR8 Active; 2.95 Å] [53] | ||
Stabilizing single-chain variable fragment scFv16 | Single-particle cryo-EM | MDMB-Fubinaca (FUB) + Gi + scFv16 [6N4B Active; 3.0 Å] [54]; | ||
Five stabilizing mutations | LCP; XRD | NAM ORG27569 [6KQI Inactive; 3.245 Å] [55]; | ||
BRIL insert in N-terminus; ; CB1-Gi stabilized by svFv16 | Single-particle cryo-EM | Agonist AM841 + Gi + svFc16 [6KPG Active; 3.00 Å] [56] | ||
Cannabinoid receptor 2 (CB2); CNR2; P34972 | Rationally designed stabilizing antagonist; T4-lysozyme insert in ICL3 | LCP; XRD | Antagonist AM10257 [5ZTY Inactive; 2.80 Å] [57]; | |
CB2-Gi stabilized by svFv16 | Cryo-EM | Agonist WIN 55,212-2 + Gi + svFv16 [6PT0 Active, 3.2 Å] [58] | ||
BRIL insert in N-terminus; CB2-Gi stabilized by svFv16 | X-ray [6KPC]; Single-particle cryo-EM | Agonist AM12033 [6KPC Active; 3.20 Å], Agonist AM12033 + Gi + svFc16 [6KPF Inactive; 2.90 Å] [56] |
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Krishna Deepak, R.N.V.; Verma, R.K.; Hartono, Y.D.; Yew, W.S.; Fan, H. Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery. Pharmaceuticals 2022, 15, 12. https://doi.org/10.3390/ph15010012
Krishna Deepak RNV, Verma RK, Hartono YD, Yew WS, Fan H. Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery. Pharmaceuticals. 2022; 15(1):12. https://doi.org/10.3390/ph15010012
Chicago/Turabian StyleKrishna Deepak, R. N. V., Ravi Kumar Verma, Yossa Dwi Hartono, Wen Shan Yew, and Hao Fan. 2022. "Recent Advances in Structure, Function, and Pharmacology of Class A Lipid GPCRs: Opportunities and Challenges for Drug Discovery" Pharmaceuticals 15, no. 1: 12. https://doi.org/10.3390/ph15010012