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- PDB-2xx8: Crystal structure of N,N-dimethyl-4-(3-(trifluoromethyl)-4,5,6,7-... -

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Basic information

Entry
Database: PDB / ID: 2xx8
TitleCrystal structure of N,N-dimethyl-4-(3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl)benzamide in complex with the ligand binding domain of the Rat GluA2 receptor and glutamate at 2.2A resolution.
ComponentsGLUTAMATE RECEPTOR 2
KeywordsTRANSPORT PROTEIN / AMPA RECEPTOR LIGAND-BINDING CORE
Function / homology
Function and homology information


spine synapse / dendritic spine cytoplasm / dendritic spine neck / cellular response to amine stimulus / dendritic spine head / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / perisynaptic space / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors ...spine synapse / dendritic spine cytoplasm / dendritic spine neck / cellular response to amine stimulus / dendritic spine head / Activation of AMPA receptors / ligand-gated monoatomic cation channel activity / perisynaptic space / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / AMPA glutamate receptor clustering / kainate selective glutamate receptor activity / immunoglobulin binding / asymmetric synapse / AMPA glutamate receptor complex / regulation of receptor recycling / extracellularly glutamate-gated ion channel activity / cellular response to glycine / ionotropic glutamate receptor complex / conditioned place preference / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / positive regulation of synaptic transmission / response to fungicide / regulation of synaptic transmission, glutamatergic / cytoskeletal protein binding / glutamate-gated receptor activity / extracellular ligand-gated monoatomic ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / regulation of long-term synaptic depression / somatodendritic compartment / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / excitatory synapse / ionotropic glutamate receptor binding / dendrite membrane / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / positive regulation of excitatory postsynaptic potential / synaptic membrane / dendritic shaft / SNARE binding / PDZ domain binding / synaptic transmission, glutamatergic / protein tetramerization / establishment of protein localization / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cerebral cortex development / receptor internalization / postsynaptic density membrane / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / terminal bouton / synaptic vesicle / long-term synaptic potentiation / synaptic vesicle membrane / amyloid-beta binding / presynapse / signaling receptor activity / growth cone / presynaptic membrane / scaffold protein binding / dendritic spine / chemical synaptic transmission / perikaryon / postsynaptic membrane / neuron projection / postsynaptic density / external side of plasma membrane / axon / neuronal cell body / synapse / dendrite / protein kinase binding / protein-containing complex binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / membrane / identical protein binding / plasma membrane
Similarity search - Function
Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Periplasmic binding protein-like II / Receptor, ligand binding region ...Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Periplasmic binding protein-like II / Receptor, ligand binding region / Receptor family ligand binding region / D-Maltodextrin-Binding Protein; domain 2 / Periplasmic binding protein-like I / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1NE / GLUTAMIC ACID / Glutamate receptor 2
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.55 Å
AuthorsWard, S.E. / Harries, M. / Aldegheri, L. / Austin, N.E. / Ballantine, S. / Ballini, E. / Bradley, D.M. / Bax, B.D. / Clarke, B.P. / Harris, A.J. ...Ward, S.E. / Harries, M. / Aldegheri, L. / Austin, N.E. / Ballantine, S. / Ballini, E. / Bradley, D.M. / Bax, B.D. / Clarke, B.P. / Harris, A.J. / Harrison, S.A. / Melarange, R.A. / Mookherjee, C. / Mosley, J. / DalNegro, G. / Oliosi, B. / Smith, K.J. / Thewlis, K.M. / Woollard, P.M. / Yusaf, S.P.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Integration of Lead Optimization with Crystallography for a Membrane-Bound Ion Channel Target: Discovery of a New Class of Ampa Receptor Positive Allosteric Modulators.
Authors: Ward, S.E. / Harries, M. / Aldegheri, L. / Austin, N.E. / Ballantine, S. / Ballini, E. / Bradley, D.M. / Bax, B.D. / Clarke, B.P. / Harris, A.J. / Harrison, S.A. / Melarange, R.A. / ...Authors: Ward, S.E. / Harries, M. / Aldegheri, L. / Austin, N.E. / Ballantine, S. / Ballini, E. / Bradley, D.M. / Bax, B.D. / Clarke, B.P. / Harris, A.J. / Harrison, S.A. / Melarange, R.A. / Mookherjee, C. / Mosley, J. / Dal Negro, G. / Oliosi, B. / Smith, K.J. / Thewlis, K.M. / Woollard, P.M. / Yusaf, S.P.
History
DepositionNov 9, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 27, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2011Group: Database references / Version format compliance
Revision 1.2Nov 20, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_entry_details.has_protein_modification / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GLUTAMATE RECEPTOR 2
B: GLUTAMATE RECEPTOR 2
C: GLUTAMATE RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,12314
Polymers87,5843
Non-polymers1,53911
Water9,044502
1
A: GLUTAMATE RECEPTOR 2
C: GLUTAMATE RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,1527
Polymers58,3892
Non-polymers7625
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2270 Å2
ΔGint-101.7 kcal/mol
Surface area22700 Å2
MethodPISA
2
B: GLUTAMATE RECEPTOR 2
hetero molecules

B: GLUTAMATE RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,94314
Polymers58,3892
Non-polymers1,55412
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
Buried area2270 Å2
ΔGint-100.5 kcal/mol
Surface area23358 Å2
MethodPISA
Unit cell
Length a, b, c (Å)113.939, 163.663, 47.379
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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Protein , 1 types, 3 molecules ABC

#1: Protein GLUTAMATE RECEPTOR 2 / GLUR-2 / AMPA-SELECTIVE GLUTAMATE RECEPTOR 2 / GLUR-B / GLUR-K2 / GLUTAMATE RECEPTOR IONOTROPIC\ / ...GLUR-2 / AMPA-SELECTIVE GLUTAMATE RECEPTOR 2 / GLUR-B / GLUR-K2 / GLUTAMATE RECEPTOR IONOTROPIC\ / AMPA 2 / GLUA2


Mass: 29194.658 Da / Num. of mol.: 3 / Fragment: LIGAND BINDING DOMAIN, RESIDUES 413-527,653-796 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: GLUA2FLOPS1-GLYTHR-S2 / Source: (gene. exp.) RATTUS NORVEGICUS (Norway rat) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P19491

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Non-polymers , 5 types, 513 molecules

#2: Chemical ChemComp-GLU / GLUTAMIC ACID


Type: L-peptide linking / Mass: 147.129 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C5H9NO4
#3: Chemical ChemComp-1NE / N,N-DIMETHYL-4-[3-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDRO-1H-INDAZOL-1-YL]BENZAMIDE


Mass: 337.340 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18F3N3O
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 502 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsENGINEERED RESIDUE IN CHAIN A, ASN 775 TO SER ENGINEERED RESIDUE IN CHAIN B, ASN 775 TO SER ...ENGINEERED RESIDUE IN CHAIN A, ASN 775 TO SER ENGINEERED RESIDUE IN CHAIN B, ASN 775 TO SER ENGINEERED RESIDUE IN CHAIN C, ASN 775 TO SER
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.52 Å3/Da / Density % sol: 51.23 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.97935
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97935 Å / Relative weight: 1
ReflectionResolution: 1.55→43.73 Å / Num. obs: 121736 / % possible obs: 94.3 % / Observed criterion σ(I): 0 / Redundancy: 4.7 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 10.4
Reflection shellResolution: 1.55→1.63 Å / Redundancy: 4.6 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 3.1 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.55→20 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.949 / SU B: 1.259 / SU ML: 0.047 / Cross valid method: THROUGHOUT / ESU R: 0.084 / ESU R Free: 0.082 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21179 6128 5 %RANDOM
Rwork0.18909 ---
obs0.19023 115490 94.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 18.347 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20 Å2
2--0.53 Å20 Å2
3----0.76 Å2
Refinement stepCycle: LAST / Resolution: 1.55→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5991 0 88 502 6581
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0226366
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6492.0968592
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5345807
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.28924.538238
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.362151167
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.0251526
X-RAY DIFFRACTIONr_chiral_restr0.1340.2945
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.024673
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2020.22916
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3060.24523
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1080.2469
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.5690.22
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2490.266
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1080.219
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0840.22
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.30924051
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.20456352
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.42162659
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.93282240
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.243 475 -
Rwork0.221 8690 -
obs--96.79 %

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