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- PDB-2xx9: Crystal structure of 1-((2-fluoro-4-(3-(trifluoromethyl)-4,5,6,7-... -

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Basic information

Entry
Database: PDB / ID: 2xx9
TitleCrystal structure of 1-((2-fluoro-4-(3-(trifluoromethyl)-4,5,6,7- tetrahydro-1H-indazol-1-yl)phenyl)methyl)-2-pyrrolidinone 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 / ION CHANNEL
Function / homology
Function and homology information


spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / kainate selective glutamate receptor activity ...spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / kainate selective glutamate receptor activity / AMPA glutamate receptor complex / cellular response to glycine / extracellularly glutamate-gated ion channel activity / ionotropic glutamate receptor complex / asymmetric synapse / immunoglobulin binding / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / glutamate receptor binding / positive regulation of synaptic transmission / response to fungicide / regulation of synaptic transmission, glutamatergic / glutamate-gated receptor activity / cytoskeletal protein binding / extracellular ligand-gated monoatomic ion channel activity / presynaptic active zone membrane / cellular response to brain-derived neurotrophic factor stimulus / glutamate-gated calcium ion channel activity / somatodendritic compartment / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / ionotropic glutamate receptor binding / dendrite membrane / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / SNARE binding / dendritic shaft / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / synaptic membrane / establishment of protein localization / modulation of chemical synaptic transmission / postsynaptic density membrane / cerebral cortex development / Schaffer collateral - CA1 synapse / receptor internalization / terminal bouton / synaptic vesicle membrane / synaptic vesicle / presynapse / signaling receptor activity / amyloid-beta binding / presynaptic membrane / growth cone / scaffold protein binding / chemical synaptic transmission / dendritic spine / perikaryon / postsynaptic membrane / neuron projection / postsynaptic density / axon / neuronal cell body / synapse / dendrite / protein-containing complex binding / protein kinase binding / glutamatergic synapse / cell surface / endoplasmic reticulum / protein-containing complex / identical protein binding / membrane / 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. / Receptor, ligand binding region / Receptor family 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. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like II / Periplasmic binding protein-like I / D-Maltodextrin-Binding Protein; domain 2 / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-1NF / GLUTAMIC ACID / Glutamate receptor 2
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.97 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 6, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2011Group: Database references / Version format compliance
Revision 1.2Oct 16, 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)89,21114
Polymers87,5843
Non-polymers1,62711
Water9,512528
1
B: GLUTAMATE RECEPTOR 2
hetero molecules

B: GLUTAMATE RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,70810
Polymers58,3892
Non-polymers1,3198
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_665-x+1,-y+1,z1
Buried area2650 Å2
ΔGint-121.1 kcal/mol
Surface area24020 Å2
MethodPISA
2
A: GLUTAMATE RECEPTOR 2
C: GLUTAMATE RECEPTOR 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,3579
Polymers58,3892
Non-polymers9687
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2110 Å2
ΔGint-41.2 kcal/mol
Surface area23010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.188, 164.152, 47.456
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, 539 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-1NF / N,N-DIMETHYL-4-[3-(TRIFLUOROMETHYL)-4,5,6,7-TETRAHYDRO-1H-INDAZOL-1-YL]BENZAMIDE


Mass: 381.367 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19F4N3O
#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.: 528 / 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: 2.56 Å3/Da / Density % sol: 51.98 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS4 / Detector: IMAGE PLATE / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.97→40 Å / Num. obs: 64133 / % possible obs: 98.9 % / Observed criterion σ(I): 0 / Redundancy: 6.5 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 13.9
Reflection shellResolution: 1.97→2 Å / Redundancy: 6.4 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 4.7 / % possible all: 98

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
HKLdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.97→94.49 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.925 / SU B: 3.616 / SU ML: 0.106 / Cross valid method: THROUGHOUT / ESU R: 0.17 / ESU R Free: 0.151 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22388 2576 4 %RANDOM
Rwork0.18522 ---
obs0.18679 61492 98.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 30.232 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2---0.23 Å20 Å2
3----0.38 Å2
Refinement stepCycle: LAST / Resolution: 1.97→94.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6046 0 94 528 6668
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0226636
X-RAY DIFFRACTIONr_bond_other_d0.0010.024536
X-RAY DIFFRACTIONr_angle_refined_deg1.4371.9898996
X-RAY DIFFRACTIONr_angle_other_deg0.9311148
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0615852
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.20624.606254
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.771151225
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2691528
X-RAY DIFFRACTIONr_chiral_restr0.0880.2972
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.027442
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021297
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8741.54109
X-RAY DIFFRACTIONr_mcbond_other0.211.51699
X-RAY DIFFRACTIONr_mcangle_it1.59126633
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.37232527
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.7944.52363
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: 1.968→2.019 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.255 187 -
Rwork0.198 4389 -
obs--98.05 %

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