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- PDB-2w3b: HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND A LIPOPHIL... -

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Basic information

Entry
Database: PDB / ID: 2w3b
TitleHUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH NADPH AND A LIPOPHILIC ANTIFOLATE SELECTIVE FOR MYCOBACTERIUM AVIUM DHFR, 6-((2,5- DIETHOXYPHENYL)AMINOMETHYL)-2,4-DIAMINO-5-METHYLPYRIDO(2,3-D) PYRIMIDINE (SRI-8686)
ComponentsDIHYDROFOLATE REDUCTASE
KeywordsOXIDOREDUCTASE / NONCLASSICAL ANTIFOLATES / ONE-CARBON METABOLISM / LIPOPHILIC ANTIFOLATES / NADP / REDUCTASE
Function / homology
Function and homology information


regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process ...regulation of removal of superoxide radicals / tetrahydrobiopterin biosynthetic process / Metabolism of folate and pterines / tetrahydrofolate metabolic process / sequence-specific mRNA binding / response to methotrexate / axon regeneration / folic acid binding / G1/S-Specific Transcription / dihydrofolate metabolic process / glycine biosynthetic process / dihydrofolate reductase / dihydrofolate reductase activity / folic acid metabolic process / NADPH binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / tetrahydrofolate biosynthetic process / mRNA regulatory element binding translation repressor activity / positive regulation of nitric-oxide synthase activity / one-carbon metabolic process / NADP binding / negative regulation of translation / mRNA binding / mitochondrion / cytosol
Similarity search - Function
Dihydrofolate Reductase, subunit A / Dihydrofolate Reductase, subunit A / Dihydrofolate reductase / Dihydrofolate reductase conserved site / Dihydrofolate reductase (DHFR) domain signature. / Dihydrofolate reductase domain / Dihydrofolate reductase / Dihydrofolate reductase (DHFR) domain profile. / Dihydrofolate reductase-like domain superfamily / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
FOLIC ACID / : / Chem-NDP / Chem-VG9 / Dihydrofolate reductase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.27 Å
AuthorsLeung, A.K.W. / Reynolds, R.C. / Borhani, D.W.
CitationJournal: To be Published
Title: Structural Basis for Selective Inhibition of Mycobacterium Avium Dihydrofolate Reductase by a Lipophilic Antifolate
Authors: Leung, A.K.W. / Ross, L.J. / Zywno-Van Ginkel, S. / Reynolds, R.C. / Seitz, L.E. / Pathak, V. / Barrow, W.W. / White, E.L. / Suling, W.J. / Piper, J.R. / Borhani, D.W.
History
DepositionNov 11, 2008Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 17, 2009Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Mar 6, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4May 8, 2019Group: Data collection / Experimental preparation
Category: database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow
Item: _exptl_crystal_grow.method
Revision 1.5May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / 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_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.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_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_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_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: DIHYDROFOLATE REDUCTASE
B: DIHYDROFOLATE REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,15010
Polymers42,9612
Non-polymers3,1898
Water10,323573
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A: DIHYDROFOLATE REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,0755
Polymers21,4811
Non-polymers1,5944
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: DIHYDROFOLATE REDUCTASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,0755
Polymers21,4811
Non-polymers1,5944
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.725, 94.387, 95.439
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11B-2263-

HOH

Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.07495, 0.996292, -0.04224), (-0.994802, -0.077632, -0.065899), (-0.068934, 0.037081, 0.996932)
Vector: -2.61422, 47.67767, 22.85954)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein DIHYDROFOLATE REDUCTASE


Mass: 21480.723 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PDFR / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P00374, dihydrofolate reductase

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Non-polymers , 5 types, 581 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-VG9 / 6-{[(2,5-DIETHOXYPHENYL)AMINO]METHYL}-5-METHYLPYRIDO[2,3-D]PYRIMIDINE-2,4-DIAMINE


Mass: 368.433 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24N6O2
#4: Chemical ChemComp-FOL / FOLIC ACID


Mass: 441.397 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H19N7O6
#5: Chemical ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: K
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 573 / Source method: isolated from a natural source / Formula: H2O

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Details

Nonpolymer details6-((2,5-DIETHOXYPHENYL)AMINOMETHYL)-2, 4-DIAMINO-5-METHYLPYRIDO(2,3-D)PYRIMIDINE (VG9): SRI-8686 ...6-((2,5-DIETHOXYPHENYL)AMINOMETHYL)-2, 4-DIAMINO-5-METHYLPYRIDO(2,3-D)PYRIMIDINE (VG9): SRI-8686 FOLIC ACID (FOL): FOLATE

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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: 2.3 Å3/Da / Density % sol: 46.61 % / Description: NONE
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.75
Details: HUMAN DHFR/FOLATE COMPLEX WAS MIXED WITH NADPH AND 6-((2,5-DIETHOXYPHENYL)AMINOMETHYL)-2, 4-DIAMINO-5-METHYLPYRIDO(2,3-D)PYRIMIDINE (SRI-8686) (BOTH 2 MM FINAL). CRYSTALS WERE GROWN BY ...Details: HUMAN DHFR/FOLATE COMPLEX WAS MIXED WITH NADPH AND 6-((2,5-DIETHOXYPHENYL)AMINOMETHYL)-2, 4-DIAMINO-5-METHYLPYRIDO(2,3-D)PYRIMIDINE (SRI-8686) (BOTH 2 MM FINAL). CRYSTALS WERE GROWN BY HANGING DROP VAPOR DIFFUSION AT 277 K BY MIXING EQUAL VOLUMES OF PROTEIN/NADPH/SRI-8686 WITH RESERVOIR (24% PEG 4000, 200 MM LI2SO4, 100 MM TRIS.HCL, PH 8.75). TRUNCATED TRIANGULAR CRYSTALS APPEARED SLOWLY, IN ABOUT A MONTH. THE CRYSTAL WAS CRYOPROTECTED WITH 15% GLYCEROL AND FLASH-COOLED IN LIQUID N2.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.785
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jan 18, 2000 / Details: MIRRORS
RadiationMonochromator: SI / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.785 Å / Relative weight: 1
ReflectionResolution: 1.25→15 Å / Num. obs: 109188 / % possible obs: 98.9 % / Observed criterion σ(I): -10 / Redundancy: 3.4 % / Biso Wilson estimate: 16.1 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 10.1
Reflection shellResolution: 1.25→1.28 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.71 / Mean I/σ(I) obs: 1.4 / % possible all: 88

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UNPUBLISHED HUMAN DHFR FOLATE COMPLEX

Resolution: 1.27→14.95 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.906 / SU ML: 0.037 / Cross valid method: THROUGHOUT / ESU R: 0.054 / ESU R Free: 0.052 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.203 5251 5.1 %RANDOM
Rwork0.171 ---
obs0.172 98560 99.8 %-
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: 16.01 Å2
Baniso -1Baniso -2Baniso -3
1--0.23 Å20 Å20 Å2
2--0.46 Å20 Å2
3----0.24 Å2
Refinement stepCycle: LAST / Resolution: 1.27→14.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2917 0 216 573 3706
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0223374
X-RAY DIFFRACTIONr_bond_other_d0.0050.022317
X-RAY DIFFRACTIONr_angle_refined_deg1.6482.054618
X-RAY DIFFRACTIONr_angle_other_deg1.22835648
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1515405
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.88724.923130
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.05815559
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.2741512
X-RAY DIFFRACTIONr_chiral_restr0.0960.2482
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023699
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02619
X-RAY DIFFRACTIONr_nbd_refined0.2250.2595
X-RAY DIFFRACTIONr_nbd_other0.2050.22413
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21602
X-RAY DIFFRACTIONr_nbtor_other0.0850.21627
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1490.2346
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2310.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2530.256
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1430.277
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.2751.51974
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.9523233
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.76831432
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.7184.51385
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: 1.27→1.3 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.295 407
Rwork0.26 7090
Refinement TLS params.

T22: -0.0334 Å2 / 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)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.1050.1095-0.05920.80130.12110.9024-0.0038-0.0632-0.0420.091-0.02-0.01740.0546-0.01270.0238-0.0388-0.0161-0.01010.0005-0.03180.61223.908-1.171
21.2455-0.21110.01551.38470.15251.7082-0.1546-0.23290.06790.11450.0608-0.05670.0384-0.09040.0938-0.00660.0594-0.0036-0.0251-0.069320.94745.20822.673
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 185
2X-RAY DIFFRACTION1A201
3X-RAY DIFFRACTION1A301
4X-RAY DIFFRACTION1A401
5X-RAY DIFFRACTION2B1 - 186
6X-RAY DIFFRACTION2B201
7X-RAY DIFFRACTION2B301
8X-RAY DIFFRACTION2B401

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