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- PDB-5vp0: Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluorom... -

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Basic information

Entry
Database: PDB / ID: 5vp0
TitleDiscovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders
ComponentscGMP-dependent 3',5'-cyclic phosphodiesterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Inhibitor / Phosphodiesterase / Brain-Pentrating / Cognitive Disorders / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier ...regulation of cGMP-mediated signaling / cellular response to 2,3,7,8-tetrachlorodibenzodioxine / cellular response to macrophage colony-stimulating factor stimulus / cellular response to cGMP / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of vascular permeability / heart valve development / cellular response to granulocyte macrophage colony-stimulating factor stimulus / negative regulation of vascular permeability / establishment of endothelial barrier / negative regulation of cAMP-mediated signaling / regulation of mitochondrion organization / aorta development / ventricular septum development / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP-mediated signaling / TPR domain binding / cGMP catabolic process / phosphate ion binding / cGMP effects / monocyte differentiation / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / regulation of cAMP-mediated signaling / cAMP binding / cellular response to cAMP / cellular response to transforming growth factor beta stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cAMP-mediated signaling / synaptic membrane / positive regulation of inflammatory response / cellular response to mechanical stimulus / cellular response to xenobiotic stimulus / presynaptic membrane / G alpha (s) signalling events / mitochondrial outer membrane / mitochondrial inner membrane / mitochondrial matrix / positive regulation of gene expression / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / magnesium ion binding / endoplasmic reticulum / protein homodimerization activity / zinc ion binding / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-9GJ / cGMP-dependent 3',5'-cyclic phosphodiesterase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsHoffman, I.D.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, ...Title: Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders.
Authors: Mikami, S. / Nakamura, S. / Ashizawa, T. / Nomura, I. / Kawasaki, M. / Sasaki, S. / Oki, H. / Kokubo, H. / Hoffman, I.D. / Zou, H. / Uchiyama, N. / Nakashima, K. / Kamiguchi, N. / Imada, H. ...Authors: Mikami, S. / Nakamura, S. / Ashizawa, T. / Nomura, I. / Kawasaki, M. / Sasaki, S. / Oki, H. / Kokubo, H. / Hoffman, I.D. / Zou, H. / Uchiyama, N. / Nakashima, K. / Kamiguchi, N. / Imada, H. / Suzuki, N. / Iwashita, H. / Taniguchi, T.
History
DepositionMay 3, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Mar 13, 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_struct_conn_angle / struct_conn / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _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.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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,34012
Polymers120,6963
Non-polymers1,6449
Water2,396133
1
A: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules

C: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,5608
Polymers80,4642
Non-polymers1,0966
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_556x+1/2,y+1/2,z+11
Buried area3170 Å2
ΔGint-115 kcal/mol
Surface area28300 Å2
MethodPISA
2
B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules

B: cGMP-dependent 3',5'-cyclic phosphodiesterase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,5608
Polymers80,4642
Non-polymers1,0966
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x,y,-z-11
Buried area3060 Å2
ΔGint-116 kcal/mol
Surface area29390 Å2
MethodPISA
Unit cell
Length a, b, c (Å)166.704, 74.265, 91.171
Angle α, β, γ (deg.)90.000, 109.770, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22C
13B
23C

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11THRTHRPHEPHEAA583 - 9159 - 341
21THRTHRPHEPHEBB583 - 9159 - 341
12ILEILELEULEUAA590 - 91616 - 342
22ILEILELEULEUCC590 - 91616 - 342
13ILEILELEULEUBB590 - 91616 - 342
23ILEILELEULEUCC590 - 91616 - 342

NCS ensembles :
ID
1
2
3

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Components

#1: Protein cGMP-dependent 3',5'-cyclic phosphodiesterase / Cyclic GMP-stimulated phosphodiesterase / cGSPDE


Mass: 40232.051 Da / Num. of mol.: 3 / Fragment: UNP residues 322-663
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE2A / Production host: Baculovirus expression vector pFastBac1-HM / Strain (production host): Sf9
References: UniProt: O00408, 3',5'-cyclic-nucleotide phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-9GJ / N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide


Mass: 458.364 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C19H18F4N4O5
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / 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: 2.2 Å3/Da / Density % sol: 44.09 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: 30% PEG3350, 0.2M MgCl2, 0.1M Tris pH 7.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 47983 / % possible obs: 90.6 % / Redundancy: 3.9 % / Rmerge(I) obs: 0.094 / Rpim(I) all: 0.052 / Rrim(I) all: 0.108 / Χ2: 1.171 / Net I/σ(I): 6.6 / Num. measured all: 188142
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.2-2.242.30.4060.8510.2790.4950.70244.5
2.24-2.282.40.4190.780.2870.510.75751.7
2.28-2.322.40.4320.8050.2970.5260.71462.4
2.32-2.372.50.4210.8360.2850.5110.71674.4
2.37-2.422.60.4080.90.2740.4940.73686.8
2.42-2.482.80.410.8980.2760.4970.71493.5
2.48-2.543.40.4020.880.250.4760.75598.8
2.54-2.613.90.3640.940.2090.4220.759100
2.61-2.694.40.3340.9520.1770.3790.756100
2.69-2.774.50.2890.9630.150.3270.768100
2.77-2.874.40.240.9650.1260.2720.787100
2.87-2.994.30.2060.9740.1110.2350.83699.9
2.99-3.124.30.1560.9780.0850.1790.9299.9
3.12-3.294.50.1220.9890.0650.1391.009100
3.29-3.494.60.1040.9920.0550.1181.182100
3.49-3.764.50.0850.9940.0450.0961.42100
3.76-4.144.30.0720.9940.0390.0821.70899.9
4.14-4.744.60.0590.9960.0320.0671.88100
4.74-5.974.40.0630.9940.0350.0731.92599.8
5.97-504.30.0520.9960.0290.062.28599.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.22data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→30 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.938 / SU B: 18.883 / SU ML: 0.211 / SU R Cruickshank DPI: 0.4013 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.401 / ESU R Free: 0.234
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.236 2360 4.9 %RANDOM
Rwork0.2113 ---
obs0.2125 45569 90.12 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 137.37 Å2 / Biso mean: 51.339 Å2 / Biso min: 19.97 Å2
Baniso -1Baniso -2Baniso -3
1--1.9 Å20 Å2-1.29 Å2
2--1.36 Å20 Å2
3---1.17 Å2
Refinement stepCycle: final / Resolution: 2.2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8060 0 102 133 8295
Biso mean--40.06 37.07 -
Num. residues----984
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0198360
X-RAY DIFFRACTIONr_bond_other_d0.0040.027847
X-RAY DIFFRACTIONr_angle_refined_deg1.3791.96111285
X-RAY DIFFRACTIONr_angle_other_deg1.385318048
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2715980
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.68223.714412
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.504151496
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1671551
X-RAY DIFFRACTIONr_chiral_restr0.080.21203
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029434
X-RAY DIFFRACTIONr_gen_planes_other0.0040.022055
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A415640.07
12B415640.07
21A388240.08
22C388240.08
31B392040.06
32C392040.06
LS refinement shellResolution: 2.203→2.26 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 86 -
Rwork0.31 1561 -
all-1647 -
obs--42.35 %
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)
13.62630.24772.09971.6940.81263.2073-0.0874-0.42490.08120.1045-0.03880.0966-0.0722-0.30730.12610.02030.021-0.00640.1064-0.00290.024518.30870.532520.3815
23.0204-0.15691.26111.1635-0.5233.0988-0.05940.06030.0299-0.0459-0.0278-0.0426-0.075-0.22020.08720.00810.0166-0.00420.0986-0.0210.008336.495-2.2049-19.3085
34.3341-0.53193.11761.7001-0.66513.6022-0.10.2630.0685-0.11810.07390.0804-0.20040.13720.02620.0625-0.0278-0.03450.1075-0.01750.05149.3345-36.45-20.6793
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A583 - 916
2X-RAY DIFFRACTION2B578 - 916
3X-RAY DIFFRACTION3C590 - 916

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