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- PDB-8zmg: Crystal structure of an inverse agonist antipsychotic drug pimava... -

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Basic information

Entry
Database: PDB / ID: 8zmg
TitleCrystal structure of an inverse agonist antipsychotic drug pimavanserin-bound 5-HT2A
Components5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / class A G protein-coupled receptor / inverse agonist
Function / homology
Function and homology information


positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / Serotonin receptors / serotonin receptor activity ...positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / Serotonin receptors / serotonin receptor activity / cell body fiber / G protein-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response / serotonin receptor signaling pathway / sensitization / urinary bladder smooth muscle contraction / neurotransmitter receptor activity / serotonin binding / negative regulation of synaptic transmission, glutamatergic / positive regulation of platelet aggregation / positive regulation of DNA biosynthetic process / temperature homeostasis / regulation of dopamine secretion / behavioral response to cocaine / negative regulation of potassium ion transport / detection of temperature stimulus involved in sensory perception of pain / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fat cell differentiation / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / dendritic shaft / positive regulation of glycolytic process / glycolytic process / electron transport chain / caveola / memory / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of neuron apoptotic process / presynaptic membrane / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / iron ion binding / response to xenobiotic stimulus / axon / neuronal cell body / positive regulation of cell population proliferation / heme binding / dendrite / protein-containing complex binding / glutamatergic synapse / identical protein binding / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
: / Soluble cytochrome b562 / 5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsOguma, T. / Asada, H. / Sekiguchi, Y. / Imono, M. / Iwata, S. / Kusakabe, K.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)22KK0099 Japan
CitationJournal: J.Med.Chem. / Year: 2024
Title: Dual 5-HT 2A and 5-HT 2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.
Authors: Oguma, T. / Jino, K. / Nakahara, K. / Asada, H. / Fuchino, K. / Nagatani, K. / Kouki, K. / Okamoto, R. / Takai, N. / Koda, K. / Fujita, S. / Sekiguchi, Y. / Yasuo, K. / Mayumi, K. / Abe, A. ...Authors: Oguma, T. / Jino, K. / Nakahara, K. / Asada, H. / Fuchino, K. / Nagatani, K. / Kouki, K. / Okamoto, R. / Takai, N. / Koda, K. / Fujita, S. / Sekiguchi, Y. / Yasuo, K. / Mayumi, K. / Abe, A. / Imono, M. / Horiguchi, N. / Iwata, S. / Kusakabe, K.I.
History
DepositionMay 23, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_contact_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _pdbx_contact_author.email
Revision 1.2Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
B: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)94,0684
Polymers93,2132
Non-polymers8552
Water00
1
A: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,0342
Polymers46,6061
Non-polymers4281
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,0342
Polymers46,6061
Non-polymers4281
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)276.260, 42.040, 90.410
Angle α, β, γ (deg.)90.000, 93.147, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y

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Components

#1: Protein 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562 / 5-HT-2 / 5-HT-2A / Serotonin receptor 2A / Cytochrome b-562


Mass: 46606.297 Da / Num. of mol.: 2 / Mutation: S162K,M164W,M29W,H124I,R128L,R315G
Source method: isolated from a genetically manipulated source
Details: Ser162Lys and Met164Trp mutations were induced in the 5-HT2A receptor and imBRIL was substituted in the 266-312 aa region of the intracellular third loop (ICL3).
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: HTR2A, HTR2, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223, UniProt: P0ABE7
#2: Chemical ChemComp-A1L11 / Pimavanserin / 1-[(4-fluorophenyl)methyl]-1-(1-methylpiperidin-4-yl)-3-[[4-(2-methylpropoxy)phenyl]methyl]urea


Mass: 427.555 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H34FN3O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.81 Å3/Da / Density % sol: 56.26 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 6 / Details: 32-38%PEG300, 40-60mM lithium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 3, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→45.14 Å / Num. obs: 14824 / % possible obs: 99.9 % / Redundancy: 20.7 % / Biso Wilson estimate: 82.5 Å2 / CC1/2: 0.982 / Rmerge(I) obs: 1.231 / Rpim(I) all: 0.2694 / Rrim(I) all: 1.246 / Net I/σ(I): 6.7
Reflection shell
Resolution (Å)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allDiffraction-ID
3.4-3.613.09124140.5840.67973.1311
3.61-3.8622290.79910.4721
3.86-4.163.8220080.9543.8691
4.16-4.561.41919180.9591.4361
4.56-5.10.84717430.9860.8581
5.1-5.890.77315570.9670.7831
5.89-7.210.53113120.9880.5371
7.21-10.20.24410470.9960.2471
10.2-45.140.1925960.9890.1941

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Processing

Software
NameVersionClassification
PHENIX1.21rc1_5127refinement
XSCALEdata scaling
XDSdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6A93

6a93


Resolution: 3.4→45.14 Å / SU ML: 0.5892 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 37.9702
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3277 1470 9.95 %
Rwork0.2907 13304 -
obs0.2943 14774 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 104.82 Å2
Refinement stepCycle: LAST / Resolution: 3.4→45.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5707 0 62 0 5769
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00235891
X-RAY DIFFRACTIONf_angle_d0.51368000
X-RAY DIFFRACTIONf_chiral_restr0.0364951
X-RAY DIFFRACTIONf_plane_restr0.0049973
X-RAY DIFFRACTIONf_dihedral_angle_d13.30412102
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.4-3.510.38231310.36011220X-RAY DIFFRACTION100
3.51-3.640.40541300.34491176X-RAY DIFFRACTION99.69
3.64-3.780.40611380.33061209X-RAY DIFFRACTION99.85
3.78-3.950.32931290.31111177X-RAY DIFFRACTION99.85
3.95-4.160.34381380.28371196X-RAY DIFFRACTION99.4
4.16-4.420.31751270.27551180X-RAY DIFFRACTION99.77
4.42-4.760.3071350.25391220X-RAY DIFFRACTION99.41
4.76-5.240.28031330.27151194X-RAY DIFFRACTION99.18
5.24-60.40631350.33011219X-RAY DIFFRACTION99.63
6-7.550.32161340.31941215X-RAY DIFFRACTION100
7.56-45.140.27561400.25091298X-RAY DIFFRACTION99.52
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.100698931762.87311937721-0.01750092029752.676588736240.1125992205252.926601564710.03143854940930.57821654621-0.07473455179980.163752228819-0.1573733182350.396828469161-0.104131225409-0.09631133247970.1754474634710.581213653298-0.467550596560.04844567326181.772789236370.5214169376511.44625370996-31.006536845314.313144752117.7287838795
25.315147408991.69251436052-0.373400571911.274028692281.113604580572.14700098690.03290135714470.680861430682-0.583689124935-0.08632312632930.0757795485888-0.590093734810.1283340101530.956309560428-0.09808025927370.118244250915-0.0609989410749-0.1379685431711.209722969220.6275107052071.2433601178-21.784564018917.234107505123.8582911139
34.149173075480.606731916798-0.952607899850.475511193552-0.4778596144381.87012130877-0.3004377294830.3361076517641.442802918150.2533566508970.1350759645350.174539668586-0.322008157488-0.43949530833-0.03722375576580.0977012159624-0.08376367172140.1123386601590.509869282728-0.04174354432411.26178118563-32.469030415819.215489650937.1102395713
41.55577609017-0.2388739473980.545862721220.717701487649-0.156881371820.9744980215790.07449680199650.436894496081-0.192727844522-0.138302963901-0.1031375194120.04014616480650.01508942316680.606386134440.03636962866730.2578684874040.1825358548260.2383300969840.4671194997610.08183523608260.977970098989-38.32682442946.2363696115940.2899165016
51.93911537701-1.683827378490.2223024883742.624240085641.004788979571.267460121310.1040224062840.08622424476750.5861506200670.2439390709610.320649285888-0.0946282362862-0.196124676590.0512708353823-0.1612261235070.3373318712220.06073212277260.0680675233330.1868194749090.09361837790951.11028892004-77.917231593710.947220428743.0903515579
68.342826934561.92936783376-1.986053608741.57974719582-0.3334965497431.62401543-0.04658602567720.953316684503-1.02685162235-0.05600948984890.197313853029-0.3322010331420.1584468667260.217511957655-0.07965648768840.54531480529-0.122466048860.1425611424310.189488606479-0.08934664347350.81210507242-49.19351672365.1298122349733.2982816087
78.346866133050.798858032081-0.1841693187714.06886411214-0.7664002872083.249951138360.02909110550550.738750510991-0.372275843369-0.2348745992410.416193091-0.69832758588-0.1000833914770.0939412444806-0.2990601684170.477962613007-0.3092558348110.2834756760651.64918275573-0.4960433599290.895466180935-28.02070695417.3884466332222.2546459054
82.40350299690.193790609690.7688509798371.00272166588-0.05152306627680.703160425502-0.141027492333-0.7154439163680.3534873307410.06993576262320.167124743305-0.04654866317940.2742262248050.7343538205650.07547743396490.09240677143060.2802839312190.376896932180.89115635646-0.06434757767521.80295534503-30.118927087716.848074604465.9070182764
90.48426815967-0.233843687738-1.04239796321.81166996282-0.7970861879193.233078920710.357346103077-1.028452610820.8459437496650.3306174643970.1072579833310.36088562547-0.358984714436-0.00299987370901-0.4203464073110.480265800442-0.02958048180580.3820204745941.59935404967-0.482493404911.72364253005-37.600629699431.02323383969.1277799958
101.19226393876-0.470851916171-0.2534319188060.2196947759660.09301812932070.6993473826380.329685794964-0.191704176797-0.273605031626-0.1097543078890.304322384981-0.3220871120740.2196187776740.5294845711510.1784000116610.1624233699230.2564737193780.295494455291.83829713852-0.1799086034261.6913327105-40.472090006122.38399835983.5415659097
114.96613517858-1.101734365681.302918812015.851636037793.12354286242.419655423660.05860802913780.0198857063944-0.1947180537310.4333809835520.172791546090.174226773601-0.202567438519-0.413458629734-0.329584500360.4622254898090.175049860192-0.01781380542291.29451590634-0.1057131056241.2986526677-80.268427649125.912016955492.9857896994
124.831828972451.06743270484-0.7338033183561.45887610899-1.517362282413.803723677090.09654154809360.4926217430860.548821114782-0.1784645099870.03924122067920.044969783385-0.0712171507682-0.387303051-0.2398051398240.742020895109-0.2057409092180.6829204125991.52180337469-0.00487985690821.56082584891-84.844922242930.108733862685.6552581011
131.33366118109-1.06825588339-0.0731467768120.9076155995740.2773383432120.7048249561520.0466111609021-0.1267739001150.274709752014-0.0168833971409-0.1191171011530.2952055661770.2589957113920.2695559822010.1044190537120.3095324969360.2052417864710.2020406536171.627273739570.1195821975590.948034890881-52.047051223317.271416430881.0089697397
140.00631455853867-0.0214467445029-0.007802942783130.2527004840460.2404148534630.260947467409-0.13626611573-1.943206724650.2709364144611.244263749170.200444524302-0.7522858801990.4462077039730.784653261036-0.04010885837181.311942777210.6661571364770.1349612939793.495476706070.02173909913922.40136160935-8.2876646734112.562956861584.4632906041
150.09790706361470.0139176113563-0.2593705836751.066126297110.1090151061630.705229908470.0483622237229-0.6550601015240.3476329806140.0753701591374-0.0123480193762-0.768993896715-0.09288072352291.10312587223-0.07221807321280.7230837653320.361975213590.2695449140641.663355437090.5289770604981.65157366229-29.46807601389.3311000958272.6960884955
162.133674017290.8715261737983.350171920511.518612884251.362068367145.25790179091-0.167189469361-0.729960638461-0.50426193115-0.03979004071250.114710536435-0.170577622060.3435264210810.4955881657390.205354236880.421002531404-0.1563404869770.145597398811.252104742260.1043293430971.36164320541-48.43903692516.9807918021658.4670839241
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 74 through 107 )AA74 - 1071 - 34
22chain 'A' and (resid 108 through 144 )AA108 - 14435 - 71
33chain 'A' and (resid 145 through 216 )AA145 - 21672 - 143
44chain 'A' and (resid 217 through 1018 )AA217 - 1018144 - 210
55chain 'A' and (resid 1019 through 1063 )AA1019 - 1063211 - 255
66chain 'A' and (resid 1064 through 348 )AA1064 - 348256 - 314
77chain 'A' and (resid 349 through 399 )AA349 - 399315 - 365
88chain 'B' and (resid 74 through 178 )BC74 - 1781 - 105
99chain 'B' and (resid 179 through 216 )BC179 - 216106 - 143
1010chain 'B' and (resid 217 through 1018 )BC217 - 1018144 - 210
1111chain 'B' and (resid 1019 through 1046 )BC1019 - 1046211 - 232
1212chain 'B' and (resid 1047 through 1063 )BC1047 - 1063233 - 249
1313chain 'B' and (resid 1064 through 348 )BC1064 - 348250 - 308
1414chain 'B' and (resid 349 through 357 )BC349 - 357309 - 317
1515chain 'B' and (resid 358 through 383 )BC358 - 383318 - 343
1616chain 'B' and (resid 384 through 401 )BC384 - 401344 - 361

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