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- PDB-9da3: Crystal structure of human DNPH1 bound to inhibitor 2a -

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Basic information

Entry
Database: PDB / ID: 9da3
TitleCrystal structure of human DNPH1 bound to inhibitor 2a
Components5-hydroxymethyl-dUMP N-hydrolase
KeywordsHYDROLASE/INHIBITOR / Inhibitor / Complex / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


purine nucleotide catabolic process / deoxyribonucleoside monophosphate catabolic process / 5-hydroxymethyl-dUMP N-hydrolase activity / nucleoside salvage / dGMP catabolic process / Purine catabolism / allantoin metabolic process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / epithelial cell differentiation / positive regulation of cell growth ...purine nucleotide catabolic process / deoxyribonucleoside monophosphate catabolic process / 5-hydroxymethyl-dUMP N-hydrolase activity / nucleoside salvage / dGMP catabolic process / Purine catabolism / allantoin metabolic process / Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds / epithelial cell differentiation / positive regulation of cell growth / protein homodimerization activity / extracellular exosome / identical protein binding / nucleus / cytoplasm / cytosol
Similarity search - Function
2-deoxynucleoside 5-phosphate N-hydrolase 1, DNPH1 / : / Nucleoside 2-deoxyribosyltransferase / Nucleoside 2-deoxyribosyltransferase
Similarity search - Domain/homology
: / 5-hydroxymethyl-dUMP N-hydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 Å
AuthorsWagner, A.G. / Schramm, V.L. / Almo, S.C. / Ghosh, A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM041916 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)S10 OD020068 United States
CitationJournal: J.Med.Chem. / Year: 2025
Title: Transition State Analogs of Human DNPH1 Reveal Two Electrophile Migration Mechanisms.
Authors: Wagner, A.G. / Lang, T.B.D. / Ledingham, E.T. / Ghosh, A. / Brooks, D. / Eskandari, R. / Suthagar, K. / Almo, S.C. / Lamiable-Oulaidi, F. / Tyler, P.C. / Schramm, V.L.
History
DepositionAug 21, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5-hydroxymethyl-dUMP N-hydrolase
B: 5-hydroxymethyl-dUMP N-hydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1174
Polymers32,4482
Non-polymers6692
Water2,990166
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Superdex S200
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4260 Å2
ΔGint-34 kcal/mol
Surface area10700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.972, 64.585, 128.640
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
11A-369-

HOH

21A-379-

HOH

31B-334-

HOH

41B-370-

HOH

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Components

#1: Protein 5-hydroxymethyl-dUMP N-hydrolase / 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 / c-Myc-responsive protein RCL


Mass: 16224.247 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DNPH1, C6orf108, RCL / Plasmid: pET-28a(+) / Details (production host): LIC / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pRIL
References: UniProt: O43598, Hydrolases; Glycosylases; Hydrolysing N-glycosyl compounds
#2: Chemical ChemComp-A1BBD / [(3R,4R)-4-hydroxy-1-{[5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]methyl}pyrrolidin-3-yl]methyl dihydrogen phosphate


Mass: 334.262 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H19N2O7P / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 166 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 1.95 Å3/Da / Density % sol: 36.97 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 5 / Details: 20% (w/v) PEG 3350 and 0.2 M Sodium malonate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jan 30, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.51→24.85 Å / Num. obs: 38634 / % possible obs: 96.9 % / Redundancy: 6.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.029 / Rrim(I) all: 0.08 / Χ2: 1.02 / Net I/σ(I): 13.4 / Num. measured all: 263117
Reflection shellResolution: 1.51→1.54 Å / % possible obs: 74.5 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.526 / Num. measured all: 5459 / Num. unique obs: 1441 / CC1/2: 0.817 / Rpim(I) all: 0.284 / Rrim(I) all: 0.601 / Χ2: 1.1 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Aimlessdata scaling
PHASERphasing
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.51→24.85 Å / SU ML: 0.16 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1982 1949 5.05 %
Rwork0.1809 --
obs0.1818 38586 96.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.51→24.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1996 0 44 166 2206
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007
X-RAY DIFFRACTIONf_angle_d1.072
X-RAY DIFFRACTIONf_dihedral_angle_d5.863306
X-RAY DIFFRACTIONf_chiral_restr0.059296
X-RAY DIFFRACTIONf_plane_restr0.018369
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.51-1.550.25021000.24551997X-RAY DIFFRACTION75
1.55-1.590.2811160.21922318X-RAY DIFFRACTION86
1.59-1.640.26891170.20042602X-RAY DIFFRACTION95
1.64-1.690.22881260.19192601X-RAY DIFFRACTION97
1.69-1.750.2571590.18762630X-RAY DIFFRACTION100
1.75-1.820.18221420.18512673X-RAY DIFFRACTION100
1.82-1.910.20571310.19612727X-RAY DIFFRACTION100
1.91-2.010.23131320.18142701X-RAY DIFFRACTION100
2.01-2.130.21421350.1862693X-RAY DIFFRACTION100
2.13-2.30.20881700.17692671X-RAY DIFFRACTION100
2.3-2.530.19091490.18252704X-RAY DIFFRACTION100
2.53-2.890.20881540.19012726X-RAY DIFFRACTION100
2.9-3.640.18311680.17822735X-RAY DIFFRACTION100
3.65-24.850.17111500.16472859X-RAY DIFFRACTION100
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)
10.70850.41130.38293.23440.04471.325-0.0423-0.04270.06480.10960.08380.1481-0.2288-0.0321-0.0190.18180.00470.01550.1644-0.02260.1305-21.4235-4.3992-6.8048
21.0419-0.28180.21051.95780.03381.2509-0.0347-0.0597-0.08450.06310.02790.5126-0.106-0.2610.020.16130.01040.01260.1938-0.01530.2267-29.1798-11.5604-12.6337
32.57720.606-0.07782.87080.53641.9264-0.05650.18810.1197-0.39430.0951-0.2507-0.25380.0971-0.06650.1924-0.02580.04450.1774-0.01410.132-15.7298-9.7954-18.7067
43.66170.53840.54993.30140.12593.969-0.2020.00410.3528-0.28640.4582-0.4787-0.90790.4581-0.02910.3732-0.09170.07930.1953-0.03010.2494-13.27283.6262-12.029
50.3210.56860.4762.74930.5963.16650.09240.783-0.8473-0.6533-0.22150.43160.1887-0.1231-0.23940.30.0215-0.04480.3653-0.22160.3643-21.5912-32.7577-27.8296
62.4039-0.71920.4114.2216-0.42812.71250.05790.114-0.24810.13020.0269-0.4299-0.01630.2159-0.10770.1372-0.00640.03120.2111-0.05280.2216-10.5539-26.9309-14.7314
71.099-0.63770.56362.4090.9053.318-0.07020.4656-0.4667-0.3462-0.1059-0.11010.12810.12480.12940.26440.02380.06420.2923-0.13010.4542-16.2838-37.1326-23.3093
84.52640.92190.84372.3680.09753.17720.04171.007-0.3595-0.91490.2537-0.2688-0.30860.44-0.2020.43760.02830.05990.4541-0.07490.224-15.8431-20.4884-31.1
92.1172-0.04560.00953.33620.13472.49430.00880.3124-0.204-0.406-0.01620.1281-0.07590.0024-0.00720.1410.0006-0.00170.173-0.04060.1329-23.8907-25.4299-20.7951
103.1665-2.1330.62193.2586-0.42592.7444-0.1493-0.1408-0.26590.29930.0156-0.05420.0180.13980.01270.1452-0.00850.02670.17990.03080.2184-21.6278-29.626-5.3472
113.2708-0.9884-0.43682.6540.31322.45650.10360.0579-0.4478-0.0971-0.05770.41430.1004-0.2554-0.03850.1119-0.0247-0.01940.1604-0.01860.2231-30.6398-29.1389-14.526
124.0479-0.98151.02254.0232-0.89618.76140.18630.0875-0.81210.19030.04290.25241.2953-0.1125-0.2590.3225-0.0397-0.01960.1911-0.08170.3827-26.1187-41.5494-18.2236
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 20 through 52 )
2X-RAY DIFFRACTION2chain 'A' and (resid 53 through 98 )
3X-RAY DIFFRACTION3chain 'A' and (resid 99 through 146 )
4X-RAY DIFFRACTION4chain 'A' and (resid 147 through 159 )
5X-RAY DIFFRACTION5chain 'B' and (resid 20 through 26 )
6X-RAY DIFFRACTION6chain 'B' and (resid 27 through 35 )
7X-RAY DIFFRACTION7chain 'B' and (resid 36 through 72 )
8X-RAY DIFFRACTION8chain 'B' and (resid 73 through 86 )
9X-RAY DIFFRACTION9chain 'B' and (resid 87 through 119 )
10X-RAY DIFFRACTION10chain 'B' and (resid 120 through 128 )
11X-RAY DIFFRACTION11chain 'B' and (resid 129 through 146 )
12X-RAY DIFFRACTION12chain 'B' and (resid 147 through 159 )

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