User:Brittany Stankavich/Sandbox 1: Difference between revisions
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hGPR40 is composed of seven-transmembrane helices that are characteristic of G-protein coupled receptors (GPCR)<ref name="crystal">PMID: 25043059</ref>. While there is relatively low sequence identity between hGPR40 and peptide-binding and opioid GPCRs, they do share structural similarities such as a conserved <scene name='72/727085/Hairpin_loop/3'>hairpin loop</scene> motif on <scene name='72/727085/Ecl2/3'>extracellular loop 2 </scene>(ECL2)<ref name="crystal"/>. In addition, there is a conserved <scene name='72/727085/Disulfide/2'>disulphide bond</scene> that is formed between transmembrane helix 3 (Cys 79) and the C-terminus of ECL2 (Cys170)<ref name="crystal"/>. Compared to peptide-binding and opioid GPCRs which have distinctive β-sheets spanning from transmembrane helix 4 to 5, hGPR40 possesses a shorter B-sheet-like region which has [http://proteopedia.org/wiki/index.php/Image:Beta-like_factors_of_hGPR40_ECL2.png low B-factors]<ref name="crystal"/>. This reflects the low mobility of the region that limits the overall flexibility of the adjacent portion of ECL2 between Leu171 and Asp175<ref name="crystal"/>. A unique feature of hGPR40 is the presence of an additional 13 residues (Pro147 to Gly159) on ECL2 which is absent on all the other peptide/opioid receptors<ref name="crystal"/>. These extra residues form a separate <scene name='72/727085/Auxiliary_loop/2'>auxiliary loop</scene> between the B-sheet-like region and transmembrane 4. Together, the auxiliary loop and ECL2 of hGPR40 function as a <scene name='72/727085/Ecl2_cap/2'>roof </scene> over the canonical binding site covering it from the central extracellular region<ref name="crystal"/>. | hGPR40 is composed of seven-transmembrane helices that are characteristic of G-protein coupled receptors (GPCR)<ref name="crystal">PMID: 25043059</ref>. While there is relatively low sequence identity between hGPR40 and peptide-binding and opioid GPCRs, they do share structural similarities such as a conserved <scene name='72/727085/Hairpin_loop/3'>hairpin loop</scene> motif on <scene name='72/727085/Ecl2/3'>extracellular loop 2 </scene>(ECL2)<ref name="crystal"/>. In addition, there is a conserved <scene name='72/727085/Disulfide/2'>disulphide bond</scene> that is formed between transmembrane helix 3 (Cys 79) and the C-terminus of ECL2 (Cys170)<ref name="crystal"/>. Compared to peptide-binding and opioid GPCRs which have distinctive β-sheets spanning from transmembrane helix 4 to 5, hGPR40 possesses a shorter B-sheet-like region which has [http://proteopedia.org/wiki/index.php/Image:Beta-like_factors_of_hGPR40_ECL2.png low B-factors]<ref name="crystal"/>. This reflects the low mobility of the region that limits the overall flexibility of the adjacent portion of ECL2 between Leu171 and Asp175<ref name="crystal"/>. A unique feature of hGPR40 is the presence of an additional 13 residues (Pro147 to Gly159) on ECL2 which is absent on all the other peptide/opioid receptors<ref name="crystal"/>. These extra residues form a separate <scene name='72/727085/Auxiliary_loop/2'>auxiliary loop</scene> between the B-sheet-like region and transmembrane 4. Together, the auxiliary loop and ECL2 of hGPR40 function as a <scene name='72/727085/Ecl2_cap/2'>roof </scene> over the canonical binding site covering it from the central extracellular region<ref name="crystal"/>. | ||
[[Image:Gpcr comparison.png|380 px|thumb|center|'''Figure 1: ''']]The canonical binding pocket for many other GPCRs is solvent exposed and centrally located between the transmembrane helices allowing ligands to directly bind from the extracellular space<ref name="crystal"/>. However, because the ECL2 acts as a roof to this canonical binding site, it inhibits ligands from entering directly from the extracellular region. Instead, the highly lipophilic nature of hGPRC40’s ligands allow it to enter a <scene name='72/727085/Hgpr40_entry/2'>noncanonical binding pocket </scene> between TM3 and TM4 by moving through the lipid bilayer<ref name="crystal"/>. | [[Image:Gpcr comparison.png|380 px|thumb|center|'''Figure 1:'''Comparison of Delta-opioid receptor to human free-fatty acid receptor (hGPR40) both of which are G-protein coupled receptors. The binding pocket of the delta-opioid receptor is solvent exposed allowing ligands to enter directly from the extracellular space while the binding pocket of hGPR40 is covered by the extracellular loop 2 (ECL2) preventing entry from the extracellular space (ECL2 represented in cyan). The Delta-opioid displays the canonical binding site typical of most GPCRs while ligands of hGPR40 bind to a noncanonical pocket represented in pink.]]The canonical binding pocket for many other GPCRs is solvent exposed and centrally located between the transmembrane helices allowing ligands to directly bind from the extracellular space<ref name="crystal"/>. However, because the ECL2 acts as a roof to this canonical binding site, it inhibits ligands from entering directly from the extracellular region. Instead, the highly lipophilic nature of hGPRC40’s ligands allow it to enter a <scene name='72/727085/Hgpr40_entry/2'>noncanonical binding pocket </scene> between TM3 and TM4 by moving through the lipid bilayer<ref name="crystal"/>. | ||
== Ligand Binding == | == Ligand Binding == | ||
