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Article ; Online: Prediction of essential binding domains for the endocannabinoid N-arachidonoylethanolamine (AEA) in the brain cannabinoid CB1 receptor.

Shim, Joong-Youn

PloS one

2021 Volume 16, Issue 6, Page(s) e0229879

Abstract: Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa (marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics pharmacological effects of endocannabinoids (eCBs) like N-arachidonylethanolamide (AEA). Due ...

Abstract	Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa (marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics pharmacological effects of endocannabinoids (eCBs) like N-arachidonylethanolamide (AEA). Due to its flexible nature of AEA structure with more than 15 rotatable bonds, establishing its binding mode to the CB1 receptor is elusive. The aim of the present study was to explore possible binding conformations of AEA within the binding pocket of the CB1 receptor confirmed in the recently available X-ray crystal structures of the CB1 receptor and predict essential AEA binding domains. We performed long time molecular dynamics (MD) simulations of plausible AEA docking poses until its receptor binding interactions became optimally established. Our simulation results revealed that AEA favors to bind to the hydrophobic channel (HC) of the CB1 receptor, suggesting that HC holds essential significance in AEA binding to the CB1 receptor. Our results also suggest that the Helix 2 (H2)/H3 region of the CB1 receptor is an AEA binding subsite privileged over the H7 region.
MeSH term(s)	Animals ; Arachidonic Acids/chemistry ; Arachidonic Acids/metabolism ; Brain/metabolism ; Cannabinoid Receptor Modulators/chemistry ; Cannabinoids/pharmacology ; Endocannabinoids/chemistry ; Endocannabinoids/metabolism ; Endocannabinoids/pharmacology ; Humans ; Molecular Docking Simulation/methods ; Molecular Dynamics Simulation ; Polyunsaturated Alkamides/chemistry ; Polyunsaturated Alkamides/metabolism ; Protein Conformation ; Protein Interaction Domains and Motifs/physiology ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/metabolism ; Receptor, Cannabinoid, CB1/ultrastructure
Chemical Substances	Arachidonic Acids ; Cannabinoid Receptor Modulators ; Cannabinoids ; Endocannabinoids ; Polyunsaturated Alkamides ; Receptor, Cannabinoid, CB1 ; anandamide (UR5G69TJKH)
Language	English
Publishing date	2021-06-28
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0229879
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Article ; Online: Prediction of essential binding domains for the endocannabinoid N-arachidonoylethanolamine (AEA) in the brain cannabinoid CB1 receptor.

Joong-Youn Shim

PLoS ONE, Vol 16, Iss 6, p e

2021 Volume 0229879

Abstract	Δ9-tetrahydrocannabinol (Δ9-THC), the main active ingredient of Cannabis sativa (marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics pharmacological effects of endocannabinoids (eCBs) like N-arachidonylethanolamide (AEA). Due to its flexible nature of AEA structure with more than 15 rotatable bonds, establishing its binding mode to the CB1 receptor is elusive. The aim of the present study was to explore possible binding conformations of AEA within the binding pocket of the CB1 receptor confirmed in the recently available X-ray crystal structures of the CB1 receptor and predict essential AEA binding domains. We performed long time molecular dynamics (MD) simulations of plausible AEA docking poses until its receptor binding interactions became optimally established. Our simulation results revealed that AEA favors to bind to the hydrophobic channel (HC) of the CB1 receptor, suggesting that HC holds essential significance in AEA binding to the CB1 receptor. Our results also suggest that the Helix 2 (H2)/H3 region of the CB1 receptor is an AEA binding subsite privileged over the H7 region.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Understanding functional residues of the cannabinoid CB1.

Shim, Joong-Youn

Current topics in medicinal chemistry

2010 Volume 10, Issue 8, Page(s) 779–798

Abstract: The brain cannabinoid (CB(1)) receptor that mediates numerous physiological processes in response to marijuana and other psychoactive compounds is a G protein coupled receptor (GPCR) and shares common structural features with many rhodopsin class GPCRs. ... ...

Abstract	The brain cannabinoid (CB(1)) receptor that mediates numerous physiological processes in response to marijuana and other psychoactive compounds is a G protein coupled receptor (GPCR) and shares common structural features with many rhodopsin class GPCRs. For the rational development of therapeutic agents targeting the CB(1) receptor, understanding of the ligand-specific CB(1) receptor interactions responsible for unique G protein signals is crucial. For a more than a decade, a combination of mutagenesis and computational modeling approaches has been successfully employed to study the ligand-specific CB(1) receptor interactions. In this review, after a brief discussion about recent advances in understanding of some structural and functional features of GPCRs commonly applicable to the CB(1) receptor, the CB(1) receptor functional residues reported from mutational studies are divided into three different types, ligand binding (B), receptor stabilization (S) and receptor activation (A) residues, to delineate the nature of the binding pockets of anandamide, CP55940, WIN55212-2 and SR141716A and to describe the molecular events of the ligand-specific CB(1) receptor activation from ligand binding to G protein signaling. Taken these CB(1) receptor functional residues, some of which are unique to the CB(1) receptor, together with the biophysical knowledge accumulated for the GPCR active state, it is possible to propose the early stages of the CB(1) receptor activation process that not only provide some insights into understanding molecular mechanisms of receptor activation but also are applicable for identifying new therapeutic agents by applying the validated structure-based approaches, such as virtual high throughput screening (HTS) and fragment-based approach (FBA).
MeSH term(s)	Animals ; Brain/drug effects ; Brain/metabolism ; Cannabinoids/chemistry ; Cannabinoids/pharmacology ; Cannabinoids/therapeutic use ; Catalytic Domain ; High-Throughput Screening Assays ; Humans ; Receptor, Cannabinoid, CB1/agonists ; Receptor, Cannabinoid, CB1/antagonists & inhibitors ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/metabolism ; Structure-Activity Relationship
Chemical Substances	Cannabinoids ; Receptor, Cannabinoid, CB1
Language	English
Publishing date	2010-04-07
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802610791164210
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Article ; Online: Transmembrane helical domain of the cannabinoid CB1 receptor.

Shim, Joong-Youn

Biophysical journal

2009 Volume 96, Issue 8, Page(s) 3251–3262

Abstract: Brain cannabinoid (CB(1)) receptors are G-protein coupled receptors and belong to the rhodopsin-like subfamily. A homology model of the inactive state of the CB(1) receptor was constructed using the x-ray structure of beta(2)-adrenergic receptor (beta(2) ... ...

Abstract	Brain cannabinoid (CB(1)) receptors are G-protein coupled receptors and belong to the rhodopsin-like subfamily. A homology model of the inactive state of the CB(1) receptor was constructed using the x-ray structure of beta(2)-adrenergic receptor (beta(2)AR) as the template. We used 105 ns duration molecular-dynamics simulations of the CB(1) receptor embedded in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer to gain some insight into the structure and function of the CB(1) receptor. As judged from the root mean-square deviations combined with the detailed structural analyses, the helical bundle of the CB(1) receptor appears to be fully converged in 50 ns of the simulation. The results reveal that the helical bundle structure of the CB(1) receptor maintains a topology quite similar to the x-ray structures of G-protein coupled receptors overall. It is also revealed that the CB(1) receptor is stabilized by the formation of extensive, water-mediated H-bond networks, aromatic stacking interactions, and receptor-lipid interactions within the helical core region. It is likely that these interactions, which are often specific to functional motifs, including the S(N)LAxAD, D(E)RY, CWxP, and NPxxY motifs, are the molecular constraints imposed on the inactive state of the CB(1) receptor. It appears that disruption of these specific interactions is necessary to release the molecular constraints to achieve a conformational change of the receptor suitable for G-protein activation.
MeSH term(s)	Binding Sites ; Computer Simulation ; Conserved Sequence ; Crystallography, X-Ray ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/metabolism ; Models, Molecular ; Phosphatidylcholines/metabolism ; Protein Conformation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/metabolism ; Receptors, Adrenergic, beta-2/chemistry ; Software ; Water/metabolism
Chemical Substances	Lipid Bilayers ; Phosphatidylcholines ; Receptor, Cannabinoid, CB1 ; Receptors, Adrenergic, beta-2 ; Water (059QF0KO0R) ; 1-palmitoyl-2-oleoylphosphatidylcholine (TE895536Y5)
Language	English
Publishing date	2009-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2008.12.3934
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Functional residues essential for the activation of the CB1 cannabinoid receptor.

Shim, Joong-Youn / Padgett, Lea

Methods in enzymology

2013 Volume 520, Page(s) 337–355

Abstract: Recently developed X-ray crystal structures of active state G-protein-coupled receptors have opened the way for detailed examination of the movement of the transmembrane (TM) helices and the specific residues involved in the receptor activation upon ... ...

Abstract	Recently developed X-ray crystal structures of active state G-protein-coupled receptors have opened the way for detailed examination of the movement of the transmembrane (TM) helices and the specific residues involved in the receptor activation upon ligand binding. Previous modeling studies have indicated that the brain cannabinoid (CB1) receptor binds with a ligand at least in part through a hydrophobic tail on the ligand. This interaction is believed to be similar to the rotameric toggle switch proposed for the β2 adrenergic receptor (β2AR). In the present study, an active state model for the CB1 receptor, guided by the X-ray structure of the active state for β2AR, was constructed with HU210 bound as a ligand. Molecular dynamics (MD) simulations were employed to provide a smooth progression between inactive and active states of the receptor. This model was compared with our previously published CB1 receptor model to identify the functional residues that play key roles in triggering receptor conformational changes upon agonist binding. Movements in TM helices and functional residues are discussed. W279(5.43), contributing to an inward movement of the fifth TM helix (TM5) to the helical core, could serve as another rotameric switch for receptor activation. V282(5.46), interacting with the ligand's hydrophobic C3 alkyl chain, appears to play a key role in TM5 inward movement centered at L286(5.50) and subsequent coupling to V204(3.40). V204(3.40), closely interacting with the TM5 and TM6 hydrophobic patch residues in the middle of the receptor, particularly I290(5.54) and L352(6.44), appears to facilitate helical rearrangements, leading to the breakage of the ionic lock and the rotameric change of Y397(7.53), which are key features of the active state.
MeSH term(s)	Animals ; Humans ; Hydrophobic and Hydrophilic Interactions ; Molecular Dynamics Simulation ; Protein Structure, Secondary ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/metabolism ; Structure-Activity Relationship
Chemical Substances	Receptor, Cannabinoid, CB1
Language	English
Publishing date	2013
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1557-7988 ; 0076-6879
ISSN (online)	1557-7988
ISSN	0076-6879
DOI	10.1016/B978-0-12-391861-1.00016-2
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Article ; Online: Computational analysis of the CB1 carboxyl-terminus in the receptor-G protein complex.

Shim, Joong-Youn / Khurana, Leepakshi / Kendall, Debra A

Proteins

2016 Volume 84, Issue 4, Page(s) 532–543

Abstract: ... the CB1 Ct can interact with the G protein by building on our prior modeling of the CB1-Gi complex (Shim ...

Abstract	Despite the important role of the carboxyl-terminus (Ct) of the activated brain cannabinoid receptor one (CB1) in the regulation of G protein signaling, a structural understanding of interactions with G proteins is lacking. This is largely due to the highly flexible nature of the CB1 Ct that dynamically adapts its conformation to the presence of G proteins. In the present study, we explored how the CB1 Ct can interact with the G protein by building on our prior modeling of the CB1-Gi complex (Shim, Ahn, and Kendall, The Journal of Biological Chemistry 2013;288:32449-32465) to incorporate a complete CB1 Ct (Glu416(Ct)-Leu472(Ct)). Based on the structural constraints from NMR studies, we employed ROSETTA to predict tertiary folds, ZDOCK to predict docking orientation, and molecular dynamics (MD) simulations to obtain two distinct plausible models of CB1 Ct in the CB1-Gi complex. The resulting models were consistent with the NMR-determined helical structure (H9) in the middle region of the CB1 Ct. The CB1 Ct directly interacted with both Gα and Gβ and stabilized the receptor at the Gi interface. The results of site-directed mutagenesis studies of Glu416(Ct), Asp423(Ct), Asp428(Ct), and Arg444(Ct) of CB1 Ct suggested that the CB1 Ct can influence receptor-G protein coupling by stabilizing the receptor at the Gi interface. This research provided, for the first time, models of the CB1 Ct in contact with the G protein.
MeSH term(s)	Amino Acid Sequence ; Analgesics/chemistry ; Binding Sites ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Cyclohexanols/chemistry ; GTP-Binding Proteins/chemistry ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism ; Gene Expression ; Guanosine 5'-O-(3-Thiotriphosphate)/chemistry ; HEK293 Cells ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Domains ; Protein Structure, Secondary ; Protein Subunits/chemistry ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Analgesics ; Cyclohexanols ; Protein Subunits ; Receptor, Cannabinoid, CB1 ; Recombinant Proteins ; Guanosine 5'-O-(3-Thiotriphosphate) (37589-80-3) ; 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol (83003-12-7) ; GTP-Binding Proteins (EC 3.6.1.-)
Language	English
Publishing date	2016-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.24999
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Article ; Online: A model for the unique role of factor Va A2 domain extension in the human ternary thrombin-generating complex.

Shim, Joong-Youn / Lee, Chang Jun / Wu, Sangwook / Pedersen, Lee G

Biophysical chemistry

2015 Volume 199, Page(s) 46–50

Abstract: An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an ... ...

Abstract	An all-atom human ternary model for the prothrombinase-prothrombin complex, including metal ions and post-translationally modified residues, was constructed from existing X-ray crystal structures. The factor Xa-prothrombin interface was taken from an existing ternary model, which locates the active site of factor Xa in the vicinity of prothrombin cleavage positions. The three sulfotyrosine residues at the C-terminal sequence of factor Va A2 domain are accommodated by modelling rational interactions with positively charged patches on the surface of prothrombin. The entire model is then solvent-equilibrated with molecular dynamics. This ternary model for the thrombin-generating complex provides an estimate as to the role of the C-terminus of the factor Va A2 domain: to establish an interface between FXa and prothrombin and to stabilize the orientation of this interface.
MeSH term(s)	Factor Va/chemistry ; Humans ; Models, Biological ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Protein Processing, Post-Translational/genetics ; Protein Structure, Tertiary/genetics ; Thrombin/chemistry
Chemical Substances	Multiprotein Complexes ; Factor Va (65522-14-7) ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2015-04
Publishing country	Netherlands
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	185052-0
ISSN	1873-4200 ; 0301-4622
ISSN (online)	1873-4200
ISSN	0301-4622
DOI	10.1016/j.bpc.2015.02.003
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Article ; Online: Do the crystallographic forms of prethrombin-2 revert to a single form in solution?

Wu, Sangwook / Shim, Joong-Youn / Lee, Chang Jun / Pedersen, Lee G

Biophysical chemistry

2015 Volume 203-204, Page(s) 28–32

Abstract: It has been earlier established (Pozzi et al. Biochemistry 50 (2011) 10195-10202) that prethrombin-2 crystallizes into two similar but distinct forms: a collapsed form and an alternative form. We employed long molecular dynamics (MD) simulations for ... ...

Abstract	It has been earlier established (Pozzi et al. Biochemistry 50 (2011) 10195-10202) that prethrombin-2 crystallizes into two similar but distinct forms: a collapsed form and an alternative form. We employed long molecular dynamics (MD) simulations for these two forms to obtain solvent-equilibrated forms. We find that, at 200ns, the simulated solution collapsed form is quite similar to the X-ray crystal collapsed form, while the simulated solution alternative form deviates from the X-ray crystal alternative form as well as from the solution collapsed form. A detailed structural analysis suggests that the fluctuation of the 140s-loop, in cross-talk with the 220s-loop, may alter the conformation of the W215-E217 segment near the nascent thrombin active site. A rationale is provided for the manner in which interactions of prethrombin-2 with FVa may affect the equilibrium between the two forms of prethrombin-2.
MeSH term(s)	Crystallography, X-Ray ; Models, Molecular ; Protein Conformation ; Prothrombin/chemistry ; Solutions
Chemical Substances	Solutions ; Prothrombin (9001-26-7) ; prethrombins (9070-19-3)
Language	English
Publishing date	2015-08
Publishing country	Netherlands
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	185052-0
ISSN	1873-4200 ; 0301-4622
ISSN (online)	1873-4200
ISSN	0301-4622
DOI	10.1016/j.bpc.2015.05.005
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Article ; Online: Molecular basis of cannabinoid CB1 receptor coupling to the G protein heterotrimer Gαiβγ: identification of key CB1 contacts with the C-terminal helix α5 of Gαi.

Shim, Joong-Youn / Ahn, Kwang H / Kendall, Debra A

The Journal of biological chemistry

2013 Volume 288, Issue 45, Page(s) 32449–32465

Abstract: The cannabinoid (CB1) receptor is a member of the rhodopsin-like G protein-coupled receptor superfamily. The human CB1 receptor, which is among the most expressed receptors in the brain, has been implicated in several disease states, including drug ... ...

Abstract	The cannabinoid (CB1) receptor is a member of the rhodopsin-like G protein-coupled receptor superfamily. The human CB1 receptor, which is among the most expressed receptors in the brain, has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. Different classes of CB1 agonists evoke signaling pathways through the activation of specific subtypes of G proteins. The molecular basis of CB1 receptor coupling to its cognate G protein is unknown. As a first step toward understanding CB1 receptor-mediated G protein signaling, we have constructed a ternary complex structural model of the CB1 receptor and Gi heterotrimer (CB1-Gi), guided by the x-ray structure of β2-adrenergic receptor (β2AR) in complex with Gs (β2AR-Gs), through 824-ns duration molecular dynamics simulations in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer environment. We identified a group of residues at the juxtamembrane regions of the intracellular loops 2 and 3 (IC2 and IC3) of the CB1 receptor, including Ile-218(3.54), Tyr-224(IC2), Asp-338(6.30), Arg-340(6.32), Leu-341(6.33), and Thr-344(6.36), as potential key contacts with the extreme C-terminal helix α5 of Gαi. Ala mutations of these residues at the receptor-Gi interface resulted in little G protein coupling activity, consistent with the present model of the CB1-Gi complex, which suggests tight interactions between CB1 and the extreme C-terminal helix α5 of Gαi. The model also suggests that unique conformational changes in the extreme C-terminal helix α5 of Gα play a crucial role in the receptor-mediated G protein activation.
MeSH term(s)	GTP-Binding Protein alpha Subunits/chemistry ; GTP-Binding Protein alpha Subunits/genetics ; GTP-Binding Protein alpha Subunits/metabolism ; GTP-Binding Protein beta Subunits/chemistry ; GTP-Binding Protein beta Subunits/genetics ; GTP-Binding Protein beta Subunits/metabolism ; GTP-Binding Protein gamma Subunits/chemistry ; GTP-Binding Protein gamma Subunits/genetics ; GTP-Binding Protein gamma Subunits/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/genetics ; Receptor, Cannabinoid, CB1/metabolism
Chemical Substances	GTP-Binding Protein alpha Subunits ; GTP-Binding Protein beta Subunits ; GTP-Binding Protein gamma Subunits ; Receptor, Cannabinoid, CB1
Language	English
Publishing date	2013-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.489153
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Article ; Online: Probing the interaction of SR141716A with the CB1 receptor.

Shim, Joong-Youn / Bertalovitz, Alexander C / Kendall, Debra A

The Journal of biological chemistry

2012 Volume 287, Issue 46, Page(s) 38741–38754

Abstract: SR141716A binds selectively to the brain cannabinoid (CB1) receptor and exhibits a potent inverse agonist/antagonist activity. Although SR141716A, also known as rimonabant, has been withdrawn from the market due to severe side effects, there remains ... ...

Abstract	SR141716A binds selectively to the brain cannabinoid (CB1) receptor and exhibits a potent inverse agonist/antagonist activity. Although SR141716A, also known as rimonabant, has been withdrawn from the market due to severe side effects, there remains interest in some of its many potential medical applications. Consequently, it is imperative to understand the mechanism by which SR141716A exerts its inverse agonist activity. As a result of using an approach combining mutagenesis and molecular dynamics simulations, we determined the binding mode of SR141716A. We found from the simulation of the CB1-SR141716A complex that SR141716A projects toward TM5 to interact tightly with the major binding pocket, replacing the coordinated water molecules, and secures the Trp-356(6.48) rotameric switch in the inactive state to promote the formation of an extensive water-mediated H-bonding network to the highly conserved SLAXAD and NPXXY motifs in TM2/TM7. We identify for the first time the involvement of the minor binding pocket formed by TM2/TM3/TM7 for SR141716A binding, which complements the major binding pocket formed by TM3/TM5/TM6. Simulation of the F174(2.61)A mutant CB1-SR141716A complex demonstrates the perturbation of TM2 that attenuates SR141716A binding indirectly. These results suggest SR141716A exerts inverse agonist activity through the stabilization of both TM2 and TM5, securing the Trp-356(6.48) rotameric switch and restraining it from activation.
MeSH term(s)	Amino Acid Sequence ; Binding Sites ; Cannabinoid Receptor Antagonists/chemistry ; Cell Membrane/metabolism ; Cholesterol/chemistry ; Humans ; Hydrogen Bonding ; Ligands ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Mutation ; Piperidines/chemistry ; Protein Binding ; Pyrazoles/chemistry ; Receptor, Cannabinoid, CB1/chemistry ; Receptors, Cannabinoid/chemistry ; Receptors, G-Protein-Coupled ; Rimonabant ; Signal Transduction
Chemical Substances	Cannabinoid Receptor Antagonists ; Ligands ; Piperidines ; Pyrazoles ; Receptor, Cannabinoid, CB1 ; Receptors, Cannabinoid ; Receptors, G-Protein-Coupled ; Cholesterol (97C5T2UQ7J) ; Rimonabant (RML78EN3XE)
Language	English
Publishing date	2012-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.390955
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