Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor.
The Histamine H(1)-receptor (H1R), belonging to the amine receptor-class of family A of the G-protein coupled receptors (GPCRs) gets activated by agonists. The consequence is a conformational change of the receptor, which may involve the binding-pocket. So, for a good prediction of the binding-mode of an agonist, it is necessary to have knowledge about these conformational changes. Meanwhile some experimental data about the structural changes of GPCRs during activation exist. Based on homology modeling of the guinea-pig H1R (gpH1R), using the crystal structure of bovine rhodopsin as template, we performed several MD simulations with distance restraints in order to get an inactive and an active structure of the gpH1R. The calculations led to a Phe6.44/Trp6.48/Phe6.52-switch and linearization of the proline kinked transmembrane helix VI during receptor activation. Our calculations showed that the Trp6.48/Phe6.52-switch induces a conformational change in Phe6.44, which slides between transmembrane helices III and VI. Additionally we observed a hydrogen bond interaction of Ser3.39 with Asn7.45 in the inactive gpH1R, but because of a counterclockwise rotation of transmembrane helix III Ser3.39 establishes a water-mediated hydrogen bond to Asp2.50 in the active gpH1R. Additionally we simulated a possible mechanism for receptor activation with a modified LigPath-algorithm.
Strasser
Andrea
A
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany. andrea.strasser@chemie.uni-regensburg.de
Wittmann
Hans-Joachim
HJ
D000818:Animals; D002417:Cattle; D003198:Computer Simulation; D006168:Guinea Pigs; D008958:Models, Molecular; D011487:Protein Conformation; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry
D011969:Receptors, Histamine H1; D012243:Rhodopsin
Biochemistry. 2001 Nov 13;40(45):13501-9
11695897
J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):673-84
17124628
J Comput Chem. 2004 Oct;25(13):1656-76
15264259
J Comput Aided Mol Des. 2006 Jul-Aug;20(7-8):449-61
17009093
J Pept Res. 2002 Dec;60(6):357-70
12464114
Proc Natl Acad Sci U S A. 2001 May 22;98(11):5997-6002
11353823
Nat Chem Biol. 2005 Jul;1(2):98-103
16408006
J Mol Biol. 2005 Apr 8;347(4):803-12
15769471
Science. 1996 Nov 1;274(5288):768-70
8864113
J Mol Model. 2007 Jan;13(1):209-18
17024405
J Med Chem. 2005 Feb 24;48(4):1088-97
15715476
J Comput Aided Mol Des. 2006 Jul-Aug;20(7-8):437-48
17103019
J Biol Chem. 2002 Oct 25;277(43):40989-96
12167654
Med Res Rev. 2001 Sep;21(5):472-83
11579443
Proteins. 2004 Jul 1;56(1):67-84
15162487
Eur J Med Chem. 2005 Jan;40(1):75-83
15642412
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
8744570
Nat Chem Biol. 2006 Aug;2(8):417-22
16799554
Endocr Rev. 2000 Feb;21(1):90-113
10696571
Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10048-53
15220479
AAPS J. 2006 May 12;8(2):E322-36
16796383
J Biol Chem. 2001 Aug 3;276(31):29171-7
11375997
Science. 2000 Aug 4;289(5480):739-45
10926528
Mol Pharmacol. 2002 May;61(5):1025-32
11961120
J Mol Biol. 2006 Mar 17;357(1):163-72
16414074
Chembiochem. 2007 Jan 2;8(1):19-24
17173267
J Biol Chem. 1998 Apr 24;273(17):10445-53
9553103
J Biol Chem. 2005 Apr 29;280(17):17135-41
15722344
J Recept Signal Transduct Res. 2003;23(2-3):123-53
14626443
Biochemistry. 2001 Dec 25;40(51):15493-500
11747424
Mol Pharmacol. 2001 Jul;60(1):1-19
11408595
Mol Pharmacol. 1998 Dec;54(6):968-78
9855624
J Biol Chem. 2006 Jun 30;281(26):18120-5
16648137
J Pharmacol Exp Ther. 2003 Jun;305(3):1104-15
12626648
J Mol Biol. 2004 Nov 5;343(5):1409-38
15491621