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6m1i

From Proteopedia

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Current revision

CryoEM structure of human PAC1 receptor in complex with PACAP38

Structural highlights

6m1i is a 6 chain structure with sequence from Camelus glama and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6m1h
Gene:	GNG2 (HUMAN), GNB1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [PACA_HUMAN] Binding to its receptor activates G proteins and stimulates adenylate cyclase in pituitary cells.^[1] [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.^[2]

Publication Abstract from PubMed

The pituitary adenylate cyclase-activating polypeptide type I receptor (PAC1R) belongs to the secretin receptor family and is widely distributed in the central neural system and peripheral organs. Abnormal activation of the receptor mediates trigeminovascular activation and sensitization, which is highly related to migraine, making PAC1R a potential therapeutic target. Elucidation of PAC1R activation mechanism would benefit discovery of therapeutic drugs for neuronal disorders. PAC1R activity is governed by pituitary adenylate cyclase-activating polypeptide (PACAP), known as a major vasodilator neuropeptide, and maxadilan, a native peptide from the sand fly, which is also capable of activating the receptor with similar potency. These peptide ligands have divergent sequences yet initiate convergent PAC1R activity. It is of interest to understand the mechanism of PAC1R ligand recognition and receptor activity regulation through structural biology. Here we report two near-atomic resolution cryo-EM structures of PAC1R activated by PACAP38 or maxadilan, providing structural insights into two distinct ligand binding modes. The structures illustrate flexibility of the extracellular domain (ECD) for ligands with distinct conformations, where ECD accommodates ligands in different orientations while extracellular loop 1 (ECL1) protrudes to further anchor the ligand bound in the orthosteric site. By structure-guided molecular modeling and mutagenesis, we tested residues in the ligand-binding pockets and identified clusters of residues that are critical for receptor activity. The structures reported here for the first time elucidate the mechanism of specificity and flexibility of ligand recognition and binding for PAC1R, and provide insights toward the design of therapeutic molecules targeting PAC1R.

Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism.,Wang J, Song X, Zhang D, Chen X, Li X, Sun Y, Li C, Song Y, Ding Y, Ren R, Harrington EH, Hu LA, Zhong W, Xu C, Huang X, Wang HW, Ma Y Cell Res. 2020 Feb 11. pii: 10.1038/s41422-020-0280-2. doi:, 10.1038/s41422-020-0280-2. PMID:32047270^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Inooka H, Ohtaki T, Kitahara O, Ikegami T, Endo S, Kitada C, Ogi K, Onda H, Fujino M, Shirakawa M. Conformation of a peptide ligand bound to its G-protein coupled receptor. Nat Struct Biol. 2001 Feb;8(2):161-5. PMID:11175907 doi:http://dx.doi.org/10.1038/84159
↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
↑ Wang J, Song X, Zhang D, Chen X, Li X, Sun Y, Li C, Song Y, Ding Y, Ren R, Harrington EH, Hu LA, Zhong W, Xu C, Huang X, Wang HW, Ma Y. Cryo-EM structures of PAC1 receptor reveal ligand binding mechanism. Cell Res. 2020 Feb 11. pii: 10.1038/s41422-020-0280-2. doi:, 10.1038/s41422-020-0280-2. PMID:32047270 doi:http://dx.doi.org/10.1038/s41422-020-0280-2

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6m1i"

@@ Line 3: / Line 3: @@
 <StructureSection load='6m1i' size='340' side='right'caption='[[6m1i]], [[Resolution|resolution]] 3.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6m1i]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M1I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6M1I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6m1i]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Camelus_glama Camelus glama] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6M1I OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6M1I FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6m1h|6m1h]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6m1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m1i OCA], [http://pdbe.org/6m1i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6m1i RCSB], [http://www.ebi.ac.uk/pdbsum/6m1i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6m1i ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GNG2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6m1i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6m1i OCA], [http://pdbe.org/6m1i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6m1i RCSB], [http://www.ebi.ac.uk/pdbsum/6m1i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6m1i ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Camelus glama]]
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Ma, Y]]

6m1i

From Proteopedia

Current revision

CryoEM structure of human PAC1 receptor in complex with PACAP38

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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