seven-transmembrane G protein-coupled receptor superfamily; This hierarchical evolutionary model represents the seven-transmembrane (7TM) receptors, often referred to as G protein-coupled receptors (GPCRs), which transmit physiological signals from the outside of the cell to the inside via G proteins. GPCRs constitute the largest known superfamily of transmembrane receptors across the three kingdoms of life that respond to a wide variety of extracellular stimuli including peptides, lipids, neurotransmitters, amino acids, hormones, and sensory stimuli such as light, smell and taste. All GPCRs share a common structural architecture comprising of seven-transmembrane (TM) alpha-helices interconnected by three extracellular and three intracellular loops. A general feature of GPCR signaling is agonist-induced conformational changes in the receptors, leading to activation of the heterotrimeric G proteins, which consist of the guanine nucleotide-binding G-alpha subunit and the dimeric G-beta-gamma subunits. The activated G proteins then bind to and activate numerous downstream effector proteins, which generate second messengers that mediate a broad range of cellular and physiological processes. However, some 7TM receptors, such as the type 1 microbial rhodopsins, do not activate G proteins. Based on sequence similarity, GPCRs can be divided into six major classes: class A (the rhodopsin-like family), class B (the Methuselah-like, adhesion and secretin-like receptor family), class C (the metabotropic glutamate receptor family), class D (the fungal mating pheromone receptors), class E (the cAMP receptor family), and class F (the frizzled/smoothened receptor family). Nearly 800 human GPCR genes have been identified and are involved essentially in all major physiological processes. Approximately 40% of clinically marketed drugs mediate their effects through modulation of GPCR function for the treatment of a variety of human diseases including bacterial infections.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  17 VLPSPNVIIILLGSLASLYVMLLLTFPSVSRKSTAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFQI 96
Cdd:cd14985   2 VIPALYIAIFLVGLLGNLFVVWVFLFPRGPKRVADIFIANLAAADLVFVLTLPLWATYTANQYDWPFGAFLCKVSSYVIS 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 85702049  97 ANIHASSLLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIWAV 142
Cdd:cd14985  82 VNMFASIFLLTCMSVDRYLAIVHPVASRRLRRRRQARVTCALIWVV 127

angiotesin receptor family and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the angiotensin receptors, the bradykinin receptors, apelin receptor as well as putative G-protein coupled receptors (GPR15 and GPR25). Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors. Ang II contributes to cardiovascular diseases such as hypertension and atherosclerosis via AT1R activation. Ang II increases blood pressure through Gq-mediated activation of phospholipase C, resulting in phosphoinositide (PI) hydrolysis and increased intracellular calcium levels. Through the AT2 receptor, Ang II counteracts the vasoconstrictor action of AT1R and thereby induces vasodilation, sodium excretion, and reduction of blood pressure. Bradykinins (BK) are pro-inflammatory peptides that mediate various vascular and pain responses to tissue injury through its B1 and B2 receptors. Apelin (APJ) receptor binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body, and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake. Orphan receptors, GPR15 and GPR25, share strong sequence homology to the angiotensin II type AT1 and AT2 receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  17 VLPSPNVIIILLGSLASLYVMLLLTFPSVSRKSTAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFQI 96
Cdd:cd14985   2 VIPALYIAIFLVGLLGNLFVVWVFLFPRGPKRVADIFIANLAAADLVFVLTLPLWATYTANQYDWPFGAFLCKVSSYVIS 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 85702049  97 ANIHASSLLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIWAV 142
Cdd:cd14985  82 VNMFASIFLLTCMSVDRYLAIVHPVASRRLRRRRQARVTCALIWVV 127

angiotesin receptor family and its related G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes the angiotensin receptors, the bradykinin receptors, apelin receptor as well as putative G-protein coupled receptors (GPR15 and GPR25). Angiotensin II (Ang II), the main effector in the renin-angiotensin system, plays a crucial role in the regulation of cardiovascular homeostasis through its type 1 (AT1) and type 2 (AT2) receptors. Ang II contributes to cardiovascular diseases such as hypertension and atherosclerosis via AT1R activation. Ang II increases blood pressure through Gq-mediated activation of phospholipase C, resulting in phosphoinositide (PI) hydrolysis and increased intracellular calcium levels. Through the AT2 receptor, Ang II counteracts the vasoconstrictor action of AT1R and thereby induces vasodilation, sodium excretion, and reduction of blood pressure. Bradykinins (BK) are pro-inflammatory peptides that mediate various vascular and pain responses to tissue injury through its B1 and B2 receptors. Apelin (APJ) receptor binds the endogenous peptide ligands, apelin and Toddler/Elabela. APJ is an adipocyte-derived hormone that is ubiquitously expressed throughout the human body, and Toddler/Elabela is a short secretory peptide that is required for normal cardiac development in zebrafish. Activation of APJ receptor plays key roles in diverse physiological processes including vasoconstriction and vasodilation, cardiac muscle contractility, angiogenesis, and regulation of water balance and food intake. Orphan receptors, GPR15 and GPR25, share strong sequence homology to the angiotensin II type AT1 and AT2 receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  17 VLPSPNVIIILLGSLASLYVMLLLTFPSVSRKSTAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFQI 96
Cdd:cd14985   2 VIPALYIAIFLVGLLGNLFVVWVFLFPRGPKRVADIFIANLAAADLVFVLTLPLWATYTANQYDWPFGAFLCKVSSYVIS 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 85702049  97 ANIHASSLLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIWAV 142
Cdd:cd14985  82 VNMFASIFLLTCMSVDRYLAIVHPVASRRLRRRRQARVTCALIWVV 127

lysophosphatidic acid receptor 4, member of the class A family of seven-transmembrane G protein-coupled receptors; Lysophosphatidic acid receptor 4 (LPAR4) is a G protein-coupled receptor that binds and is activated by the bioactive lipid lysophosphatidic acid (LPA), which is released by activated platelets and constitutively found in serum. Phylogenetic analysis of the class A GPCRs shows that LAPR4 is classified into the cluster consisting receptors that are preferentially activated by adenosine and uridine nucleotides. Although LPA6 (P2Y5) is expressed in human hair follicle cells, LPA4 and LPA5 are not. These three receptors are highly homologous and mediate an increase in intracellular cAMP production. Activation of LPAR5 is coupled to G(12/13) proteins, leading to neurite retraction and stress fiber formation, whereas coupling to G(q) protein leads to increases in calcium levels.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  24 IIILLGSLASLYVMLLLTFPSVSRKSTAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFqIANIHASS 103
Cdd:cd15155   9 VVFILGLITNCASLFVFCFRMKMRNETAIFMTNLAVSDLLFVFTLPFKIFYNFNRHWPFGDSLCKISGTAF-LTNIYGSM 87

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 85702049 104 LLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIWAVVIT 145
Cdd:cd15155  88 LFLTCISVDRFLAIVYPFRSRTIRTRRNSAIVCAGVWILVLS 129

G protein-coupled receptor 15, member of the class A family of seven-transmembrane G protein-coupled receptors; GPR15, also called as Brother of Bonzo (BOB), is an orphan G-protein coupled receptor that was originally identified as a co-receptor for human immunodeficiency virus. GPR15 is upregulated in patients with rheumatoid arthritis and shares high sequence homology with angiotensin II type AT1 and AT2 receptors; however, its endogenous ligand is unknown. GPR15 controls homing of T cells, especially FOXP3(+) regulatory T cells, to the large intestine mucosa and thereby mediates local immune homeostasis. Moreover, GRP15-deficient mice were shown to be prone to develop more severe large intestine inflammation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  18 LPSPNVIIILLGSLASLYVMLLLTFPSVSRKSTAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFQIA 97
Cdd:cd15194   3 LPILYCLVFLVGAVGNAILMGALVFKRGVRRLIDIFISNLAASDFIFLVTLPLWVDKEVVLGPWRSGSFLCKGSSYIISV 82

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 85702049  98 NIHASSLLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIW 140
Cdd:cd15194  83 NMYCSVFLLTCMSLDRYLAIVLPLVSRKFRTKHNAKVCCTCVW 125

P2Y purinoceptors 6 and 3, and similar proteins, member of the class A family of seven-transmembrane G protein-coupled receptors; This group includes P2Y receptor 6 (P2Y6), P2Y3, and P2Y3-like proteins. These receptors belong to the G(i) class of a family of purinergic G-protein coupled receptors. In the CNS, P2Y6 plays a role in microglia activation and phagocytosis, and is involved in the secretion of interleukin from monocytes and macrophages in the immune system. The P2Y receptor family is composed of eight subtypes, which are activated by naturally occurring extracellular nucleotides such as ATP, ADP, UTP, UDP, and UDP-glucose. These eight receptors are ubiquitous in human tissues and can be further classified into two subfamilies based on sequence homology and second messenger coupling: a subfamily of five P2Y1-like receptors (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11Rs) that are coupled to G(q) protein to activate phospholipase C (PLC) and a second subfamily of three P2Y12-like receptors (P2Y12, P2YR13, and P2Y14Rs) that are coupled to G(i) protein to inhibit adenylate cyclase. Several cloned subtypes, such as P2Y3, P2Y5, and P2Y7-10, are not functional mammalian nucleotide receptors. The native agonists for P2Y receptors are: ATP (P2Y2, P2Y12), ADP (P2Y1, P2Y12, and P2Y13), UTP (P2Y2, P2Y4), UDP (P2Y6, P2Y14), and UDP-glucose (P2Y14).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 85702049  50 TAVFIGSIAQADILVVCSLFSAISACVIRSEPSSTSFQLALRQNFQIANIHASSLLLSCVTLEAFLITFLPVETRHIRNV 129
Cdd:cd15968  35 TAIYMVNLALADLLYALSLPLLIYNYAMRDRWLFGDFMCRLVRFLFYFNLYGSILFLTCISVHRYLGICHPMRPWHKETR 114

                        90
                ....*....|....*...
gi 85702049 130 RCARVASKIIWAVVITEC 147
Cdd:cd15968 115 RAAWLTCVLVWILVFAQT 132

proton-sensing G protein-coupled receptors, member of the class A family of seven-transmembrane G protein-coupled receptors; Proton/pH-sensing G-protein coupled receptors sense pH of 7.6 to 6.0. They mediate a variety of biological activities in neutral and mildly acidic pH conditions, whereas the acid-sensing ionotropic ion channels typically sense strong acidic pH. The proton/pH-sensing receptor family includes the G2 accumulation receptor (G2A, also known as GPR132), the T cell death associated gene-8 (TDAG8, GPR65) receptor, ovarian cancer G-protein receptor 1 (OGR-1, GPR68), and G-protein-coupled receptor 4 (GPR4).

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 85702049  94 FQIANIHASSLLLSCVTLEAFLITFLPVETRHIRNVRCARVASKIIWAVV 143
Cdd:cd15160  79 FFYTNIYASIGFLCCIAVDRYLAVVHPLRFRGLRTRRFALKVSASIWVLE 128