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- PDB-6hlp: Crystal structure of the Neurokinin 1 receptor in complex with th... -

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Basic information

Entry
Database: PDB / ID: 6hlp
TitleCrystal structure of the Neurokinin 1 receptor in complex with the small molecule antagonist Netupitant
ComponentsSubstance-P receptor,Substance-P receptor
KeywordsMEMBRANE PROTEIN / 7-TM / GPCR / Signalling protein
Function / homology
Function and homology information


substance P receptor activity / tachykinin receptor activity / positive regulation of flagellated sperm motility / aggressive behavior / Tachykinin receptors bind tachykinins / sperm ejaculation / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning ...substance P receptor activity / tachykinin receptor activity / positive regulation of flagellated sperm motility / aggressive behavior / Tachykinin receptors bind tachykinins / sperm ejaculation / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning / positive regulation of lymphocyte proliferation / tachykinin receptor signaling pathway / alpha-1,4-glucan glucosyltransferase (UDP-glucose donor) activity / response to ozone / sperm head / positive regulation of action potential / response to auditory stimulus / positive regulation of blood pressure / smooth muscle contraction involved in micturition / regulation of smooth muscle cell proliferation / positive regulation of vascular permeability / positive regulation of hormone secretion / positive regulation of ossification / regulation of smooth muscle cell migration / positive regulation of leukocyte migration / eating behavior / positive regulation of vasoconstriction / behavioral response to pain / angiotensin-mediated drinking behavior / associative learning / positive regulation of epithelial cell migration / response to electrical stimulus / long-term memory / sperm flagellum / positive regulation of stress fiber assembly / sperm midpiece / response to progesterone / positive regulation of epithelial cell proliferation / positive regulation of synaptic transmission, GABAergic / response to nicotine / response to estradiol / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / positive regulation of cytosolic calcium ion concentration / cell body / response to ethanol / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / postsynaptic membrane / inflammatory response / dendrite / cell surface / plasma membrane
Similarity search - Function
Neurokinin NK1 receptor / Neurokinin receptor / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycosyl transferases group 1 / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM ...Neurokinin NK1 receptor / Neurokinin receptor / Glycosyl transferases group 1 / Bacterial/plant glycogen synthase / Starch synthase, catalytic domain / Starch synthase catalytic domain / Glycosyl transferases group 1 / 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
CITRIC ACID / Chem-GAW / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Substance-P receptor / Glycogen synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Pyrococcus abyssi GE5 (archaea)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsSchoppe, J. / Ehrenmann, J. / Klenk, C. / Rucktooa, P. / Schutz, M. / Dore, A.S. / Pluckthun, A.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Swiss National Science Foundation31003A_153143 Switzerland
CitationJournal: Nat Commun / Year: 2019
Title: Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists.
Authors: Schoppe, J. / Ehrenmann, J. / Klenk, C. / Rucktooa, P. / Schutz, M. / Dore, A.S. / Pluckthun, A.
History
DepositionSep 11, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 16, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Substance-P receptor,Substance-P receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,50443
Polymers59,1481
Non-polymers8,35642
Water1,33374
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein elutes as a monomeric peak on size exclusion chromatography.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9630 Å2
ΔGint66 kcal/mol
Surface area24330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)61.658, 76.571, 166.035
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Substance-P receptor,Substance-P receptor / SPR / NK-1 receptor / NK-1R / Tachykinin receptor 1


Mass: 59148.160 Da / Num. of mol.: 1
Mutation: L74A; V116I; A144L; M181K; A215L; W224R; K243A,L74A; V116I; A144L; M181K; A215L; W224R; K243A,L74A; V116I; A144L; M181K; A215L; W224R; K243A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Pyrococcus abyssi GE5 (archaea)
Gene: TACR1, NK1R, TAC1R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25103, UniProt: Q9V2J8

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Non-polymers , 6 types, 116 molecules

#2: Chemical ChemComp-GAW / 2-[3,5-bis(trifluoromethyl)phenyl]-~{N},2-dimethyl-~{N}-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide


Mass: 578.592 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H32F6N4O
#3: Chemical ChemComp-CIT / CITRIC ACID


Mass: 192.124 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H8O7
#4: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C18H34O2
#5: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical...
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: C4H10O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 74 / Source method: isolated from a natural source / Formula: H2O

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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: 3.58 Å3/Da / Density % sol: 65.67 % / Description: Star-shaped.
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 6
Details: 100 mM sodium citrate pH 6.0, 31% (v/v) PEG400, 40-50 mM Mg(HCO2)2 and 50 uM netupitant

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.06795 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: May 17, 2018 / Details: mirrors
RadiationMonochromator: Si / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.06795 Å / Relative weight: 1
ReflectionResolution: 2.2→49.5 Å / Num. obs: 40792 / % possible obs: 99.9 % / Redundancy: 18.5 % / CC1/2: 0.998 / Rpim(I) all: 0.039 / Net I/σ(I): 11.9
Reflection shellResolution: 2.2→2.27 Å / Redundancy: 18.8 % / Mean I/σ(I) obs: 1.3 / Num. unique obs: 3452 / CC1/2: 0.666 / Rpim(I) all: 0.747 / % possible all: 99.4

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZJC

4zjc


Resolution: 2.2→29.236 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2251 1977 4.86 %
Rwork0.2026 --
obs0.2037 40668 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→29.236 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3882 0 440 74 4396
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0044385
X-RAY DIFFRACTIONf_angle_d0.7015810
X-RAY DIFFRACTIONf_dihedral_angle_d16.5642602
X-RAY DIFFRACTIONf_chiral_restr0.047622
X-RAY DIFFRACTIONf_plane_restr0.005689
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2001-2.25510.30591230.29852697X-RAY DIFFRACTION100
2.2551-2.31610.31241230.27552726X-RAY DIFFRACTION100
2.3161-2.38420.36931480.2652738X-RAY DIFFRACTION100
2.3842-2.46110.26621370.24462739X-RAY DIFFRACTION100
2.4611-2.54910.281330.2292715X-RAY DIFFRACTION100
2.5491-2.6510.1931450.21482742X-RAY DIFFRACTION100
2.651-2.77160.2471430.19842721X-RAY DIFFRACTION100
2.7716-2.91760.24611440.2012758X-RAY DIFFRACTION100
2.9176-3.10020.21241290.2072767X-RAY DIFFRACTION100
3.1002-3.33930.22851660.2162742X-RAY DIFFRACTION100
3.3393-3.67470.25221520.20082765X-RAY DIFFRACTION100
3.6747-4.20510.21041410.18352784X-RAY DIFFRACTION100
4.2051-5.29290.16791310.18012847X-RAY DIFFRACTION100
5.2929-29.2390.22381620.19412950X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 3.9767 Å / Origin y: -11.0651 Å / Origin z: 57.5226 Å
111213212223313233
T0.4174 Å20.0011 Å2-0.0092 Å2-0.4087 Å2-0.031 Å2--0.4743 Å2
L0.3916 °2-0.1394 °20.348 °2-1.1169 °2-1.5416 °2--2.8662 °2
S0.0372 Å °-0.0375 Å °0.0181 Å °-0.0056 Å °0.0042 Å °0.0155 Å °0.0462 Å °0.0605 Å °0.0001 Å °
Refinement TLS groupSelection details: all

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