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- PDB-4g2l: Human PDE9 in complex with selective compound -

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Basic information

Entry
Database: PDB / ID: 4g2l
TitleHuman PDE9 in complex with selective compound
ComponentsHigh affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / phosphodiesterase / inhibitor complex / cGMP->GMP / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling ...cGMP metabolic process / negative regulation of neural precursor cell proliferation / 3',5'-cyclic-GMP phosphodiesterase / positive regulation of cardiac muscle hypertrophy / cGMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / positive regulation of long-term synaptic potentiation / sarcolemma / ruffle membrane / perikaryon / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / signal transduction / nucleoplasm / identical protein binding / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-0WL / High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 3 Å
AuthorsLiu, S.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Application of structure-based drug design and parallel chemistry to identify selective, brain penetrant, in vivo active phosphodiesterase 9A inhibitors.
Authors: Claffey, M.M. / Helal, C.J. / Verhoest, P.R. / Kang, Z. / Fors, K.S. / Jung, S. / Zhong, J. / Bundesmann, M.W. / Hou, X. / Lui, S. / Kleiman, R.J. / Vanase-Frawley, M. / Schmidt, A.W. / ...Authors: Claffey, M.M. / Helal, C.J. / Verhoest, P.R. / Kang, Z. / Fors, K.S. / Jung, S. / Zhong, J. / Bundesmann, M.W. / Hou, X. / Lui, S. / Kleiman, R.J. / Vanase-Frawley, M. / Schmidt, A.W. / Menniti, F. / Schmidt, C.J. / Hoffman, W.E. / Hajos, M. / McDowell, L. / O'Connor, R.E. / Macdougall-Murphy, M. / Fonseca, K.R. / Becker, S.L. / Nelson, F.R. / Liras, S.
History
DepositionJul 12, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 28, 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 / struct_ref_seq_dif / struct_site
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_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.ptnr2_auth_asym_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.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 / _struct_ref_seq_dif.details / _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: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,6368
Polymers77,7262
Non-polymers9106
Water00
1
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3184
Polymers38,8631
Non-polymers4553
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,3184
Polymers38,8631
Non-polymers4553
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
A: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules

B: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,6368
Polymers77,7262
Non-polymers9106
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_645-y+3/2,x-1/2,z+1/41
Buried area2840 Å2
ΔGint-111 kcal/mol
Surface area28330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.226, 104.226, 270.476
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Ens-ID: 1 / Refine code: 2

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLYGLYGLNGLNAA178 - 4271 - 250
21GLYGLYGLNGLNBB178 - 4271 - 250
12THRTHRASPASPAA448 - 488271 - 311
22THRTHRASPASPBB448 - 488271 - 311

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Components

#1: Protein High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A


Mass: 38862.926 Da / Num. of mol.: 2 / Fragment: UNP Residues 242-566
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE9A
References: UniProt: O76083, 3',5'-cyclic-GMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-0WL / 1-cyclopentyl-6-{(1R)-1-[3-(pyrimidin-2-yl)azetidin-1-yl]ethyl}-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 365.432 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N7O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 4.73 Å3/Da / Density % sol: 73.97 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→50 Å / Num. all: 30918 / Num. obs: 30608 / % possible obs: 99 % / Observed criterion σ(I): 2

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Processing

SoftwareName: REFMAC / Version: 5.2.0019 / Classification: refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 3→49.81 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.916 / SU B: 25.322 / SU ML: 0.199 / Cross valid method: THROUGHOUT / ESU R: 0.567 / ESU R Free: 0.299 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21439 3148 10.3 %RANDOM
Rwork0.18244 ---
obs0.18585 27383 99.15 %-
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: 37.088 Å2
Baniso -1Baniso -2Baniso -3
1-1.76 Å20 Å20 Å2
2--1.76 Å20 Å2
3----3.52 Å2
Refinement stepCycle: LAST / Resolution: 3→49.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5412 0 58 0 5470
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0225614
X-RAY DIFFRACTIONr_bond_other_d0.0020.023842
X-RAY DIFFRACTIONr_angle_refined_deg1.8691.9667608
X-RAY DIFFRACTIONr_angle_other_deg1.05839362
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1895654
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.57824.317278
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.731151000
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4011532
X-RAY DIFFRACTIONr_chiral_restr0.0920.2814
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.026176
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021140
X-RAY DIFFRACTIONr_nbd_refined0.2530.21448
X-RAY DIFFRACTIONr_nbd_other0.1980.23896
X-RAY DIFFRACTIONr_nbtor_refined0.2050.22801
X-RAY DIFFRACTIONr_nbtor_other0.0980.22904
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.140.283
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.270.213
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2650.229
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.220.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8621.54211
X-RAY DIFFRACTIONr_mcbond_other0.1391.51288
X-RAY DIFFRACTIONr_mcangle_it1.03925380
X-RAY DIFFRACTIONr_scbond_it1.8932700
X-RAY DIFFRACTIONr_scangle_it2.9434.52224
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
1723tight positional0.060.05
2334medium positional0.320.5
1723tight thermal0.110.5
2334medium thermal0.542
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.313 195 -
Rwork0.312 2042 -
obs--99.55 %
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)
11.2935-0.4734-0.14461.40990.20371.77110.0631-0.0860.0580.0452-0.02860.1823-0.2087-0.1372-0.0345-0.00690.003-0.0036-0.1939-0.0009-0.090884.6645.816945.6683
20.8628-0.31130.31331.5517-0.24391.84160.02330.1502-0.0991-0.0659-0.0562-0.01010.15880.07670.0329-0.10710.02770.0288-0.1147-0.0157-0.087193.139832.00326.8966
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A181 - 505
2X-RAY DIFFRACTION1A901 - 903
3X-RAY DIFFRACTION2B181 - 505
4X-RAY DIFFRACTION2B901 - 903

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