Homology modeling and molecular docking of human pituitary adenylate cyclase‑activating polypeptide I receptor

Wu,Lusheng; Guang,Wenhua; Chen,Xiaojia; Hong,An

doi:10.3892/mmr.2014.2419

Homology modeling and molecular docking of human pituitary adenylate cyclase‑activating polypeptide I receptor

Authors:
- Lusheng Wu
- Wenhua Guang
- Xiaojia Chen
- An Hong
View Affiliations

Affiliations: Biomedicine Institute, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, P.R. China
Published online on: July 24, 2014 https://doi.org/10.3892/mmr.2014.2419
Pages: 1691-1696
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Pituitary adenylate cyclase‑activating peptide I receptor (PAC1R) is member of the B class of G protein‑coupled seven‑transmembrane receptors, with molecular functions associated with neural cell differentiation, regeneration and the inhibition of apoptosis. However, the integrity of the protein structure is difficult to be determined in vitro. In the present study, the physicochemical properties of PAC1R were analyzed, the extracellular, transmembrane and intracellular regions were constructed and a three‑dimensional structure model of PAC1R was produced using extracellular loop region optimization and the energy minimization homology modeling method. Preliminary studies on the PAC1R protein and ligand interactions used a molecular docking method. The results indicated that the interaction sites of PAC1R were at Ile63, Ser100 and Gln105. These were the sites where the PAC1R combined with a hydrazide small molecule inhibitor. This study provides a theoretical basis for further studies on the model for the development of PAC1R target drugs.

View Figures

View References

1	Henle F, Fischer C, Meyer DK and Leemhuis J: Vasoactive intestinal peptide and PACAP38 control N-methyl-D-aspartic acid-induced dendrite motility by modifying the activities of Rho GTPases and phosphatidylinositol 3-kinases. J Biol Chem. 281:24955–24969. 2006. View Article : Google Scholar
2	Kimura H, Kawatani M, Ito E and Ishikawa K: PACAP facilitate the nerve regeneration factors in the facial nerve injury. Regul Pept. 123:135–138. 2004. View Article : Google Scholar : PubMed/NCBI
3	May V, Lutz E, MacKenzie C, Schutz KC, Dozark K and Braas KM: Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem. 285:9749–9761. 2010. View Article : Google Scholar
4	Bourgault S, Vaudry D, Botia B, et al: Novel stable PACAP analogs with potent activity towards the PAC1 receptor. Peptides. 29:919–932. 2008. View Article : Google Scholar : PubMed/NCBI
5	Schmidt DT, Rühlmann E, Waldeck B, et al: The effect of the vasoactive intestinal polypeptide agonist Ro 25–1553 on induced tone in isolated human airways and pulmonary artery. Naunyn Schmiedebergs Arch Pharmacol. 364:314–320. 2001.
6	Deutsch PJ and Sun Y: The 38-amino acid form of pituitary adenylate cyclase-activating polypeptide stimulates dual signaling cascades in PC12 cells and promotes neurite outgrowth. J Biol Chem. 267:5108–5113. 1992.
7	Deutsch PJ, Schadlow VC and Barzilai N: 38-Amino acid form of pituitary adenylate cyclase activating peptide induces process outgrowth in human neuroblastoma cells. J Neurosci Res. 35:312–320. 1993. View Article : Google Scholar : PubMed/NCBI
8	Rawlings SR: PACAP, PACAP receptors, and intracellular signalling. Mol Cell Endocrinol. 101:C5–C9. 1994. View Article : Google Scholar : PubMed/NCBI
9	Fukiage C, Nakajima T, Takayama Y, Minagawa Y, Shearer TR and Azuma M: PACAP induces neurite outgrowth in cultured trigeminal ganglion cells and recovery of corneal sensitivity after flap surgery in rabbits. Am J Ophthalmol. 143:255–262. 2007. View Article : Google Scholar
10	Klabunde T and Hessler G: Drug design strategies for targeting G-protein-coupled receptors. Chembiochem. 3:928–944. 2002. View Article : Google Scholar : PubMed/NCBI
11	Sun C, Song D, Davis-Taber RA, et al: Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-RS. Proc Natl Acad Sci USA. 104:7875–7880. 2007. View Article : Google Scholar
12	Kumar S, Pioszak A, Zhang C, Swaminathan K and Xu HE: Crystal structure of the PAC1R extracellular domain unifies a consensus fold for hormone recognition by class B G-protein coupled receptors. PLoS One. 6:e196822011. View Article : Google Scholar : PubMed/NCBI
13	Beebe X, Darczak D, Davis-Taber RA, et al: Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC1-R). Bioorg Med Chem Lett. 18:2162–2166. 2008. View Article : Google Scholar : PubMed/NCBI
14	Wilkins MR, Gasteiger E, Bairoch A, et al: Protein identification and analysis tools in the ExPASy server. Methods Mol Biol. 112:531–552. 1999.PubMed/NCBI
15	Dautzenberg FM, Mevenkamp G, Wille S and Hauger RL: N-terminal splice variants of the type I PACAP receptor: isolation, characterization and ligand binding/selectivity determinants. J Neuroendocrinol. 11:941–949. 1999. View Article : Google Scholar
16	Kufareva I, Rueda M, Katritch V, Stevens RC and Abagyan R; GPCP Dock 2010 participants. Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. Structure. 19:1108–1126. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhang Y, Yang HQ, Li J and Fang HS: Homology modeling of three-dimensional structure of human CCR5. Pharmaceutical Biotechnology. 19:432–436. 2012.(In Chinese).
18	Lin KJ, Zhu DJ, Leng YG and You QD: Structural characterization of human parathyroid hormone 1 receptor. Acta Phys Chim Sin. 28:1783–1789. 2012.
19	Mirzadegan T, Benkö G, Filipek S and Palczewski K: Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. Biochemistry. 42:2759–2767. 2003. View Article : Google Scholar
20	Bowie JU, Lüthy R and Eisenberg D: A method to identify protein sequences that fold into a known three-dimensional structure. Science. 253:164–170. 1991. View Article : Google Scholar : PubMed/NCBI
21	Seaborn T, Masmoudi-Kouli O, Fournier A, Vaudry H and Vaudry D: Protective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) against apoptosis. Curr Pharm Des. 17:204–214. 2011. View Article : Google Scholar : PubMed/NCBI
22	Fila T, Trazzi S, Crochemore C, Bartesaghi R and Ciani E: Lot1 is a key element of the pituitary adenylate cyclase-activating polypeptide (PACAP)/cyclic AMP pathway that negatively regulates neuronal precursor proliferation. J Biol Chem. 284:15325–15338. 2009. View Article : Google Scholar
23	Deguil J, Jailloux D, Page G, et al: Neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in MPP⁺-induced alteration of translational control in Neuro-2a neuroblastoma cells. J Neurosci Res. 85:2017–2025. 2007. View Article : Google Scholar : PubMed/NCBI
24	Somogyvári-Vigh A and Reglodi D: Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Curr Pharm Des. 10:2861–2889. 2004.PubMed/NCBI
25	Hruby VJ: Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov. 1:847–858. 2002. View Article : Google Scholar : PubMed/NCBI
26	Palczewski K, Kumasaka T, Hori T, et al: Crystal structure of rhodopsin: a G protein-coupled receptor. Science. 289:739–745. 2000. View Article : Google Scholar
27	Elbegdorj O, Westkaemper RB and Zhang Y: A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55. J Mol Graph Model. 39:50–60. 2013. View Article : Google Scholar
28	Okada T, Sugihara M, Bondar AN, Elstner M, Entel P and Buss V: The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure. J Mol Biol. 342:571–583. 2004. View Article : Google Scholar
29	Tibaduiza EC, Chen C and Beinborn M: A small molecule ligand of the glucagon-like peptide 1 receptor targets its amino-terminal hormone binding domain. J Biol Chem. 276:37787–37793. 2001.PubMed/NCBI