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- PDB-7ulu: Human DDAH1 soaked with its inhibitor ClPyrAA -

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Basic information

Entry
Database: PDB / ID: 7ulu
TitleHuman DDAH1 soaked with its inhibitor ClPyrAA
ComponentsN(G),N(G)-dimethylarginine dimethylaminohydrolase 1
KeywordsHYDROLASE / DDAH1 / Dimethylargininase / DDAH / ClPyrAA
Function / homology
Function and homology information


dimethylargininase / dimethylargininase activity / citrulline metabolic process / negative regulation of cellular response to hypoxia / arginine metabolic process / regulation of systemic arterial blood pressure / negative regulation of vascular permeability / nitric oxide metabolic process / amino acid binding / nitric oxide mediated signal transduction ...dimethylargininase / dimethylargininase activity / citrulline metabolic process / negative regulation of cellular response to hypoxia / arginine metabolic process / regulation of systemic arterial blood pressure / negative regulation of vascular permeability / nitric oxide metabolic process / amino acid binding / nitric oxide mediated signal transduction / catalytic activity / eNOS activation / arginine catabolic process / positive regulation of angiogenesis / positive regulation of nitric oxide biosynthetic process / negative regulation of cell population proliferation / extracellular exosome / metal ion binding / cytosol
Similarity search - Function
Dimethylarginine dimethylaminohydrolase / N,N dimethylarginine dimethylhydrolase, eukaryotic
Similarity search - Domain/homology
(2S)-2-amino-4-[(pyridin-2-yl)amino]butanoic acid / N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsButrin, A. / Zheng, Y. / Tuley, A. / Liu, D. / Fast, W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)CHE-1904514 United States
CitationJournal: To Be Published
Title: Optimization of a switchable electrophile fragment into a potent and selective covalent inhibitor of human DDAH1
Authors: Tuley, A. / Zheng, Y. / Tommasi, S. / Butrin, A. / May, K.V. / Ahn, Y. / Reidl, T.C. / Weerakoon, L. / Hulin, J. / Meech, R. / Patel, D.S. / Horton, C.P. / Swartzel, C.J. / Kim, Y. / ...Authors: Tuley, A. / Zheng, Y. / Tommasi, S. / Butrin, A. / May, K.V. / Ahn, Y. / Reidl, T.C. / Weerakoon, L. / Hulin, J. / Meech, R. / Patel, D.S. / Horton, C.P. / Swartzel, C.J. / Kim, Y. / Silverman, B.R. / Mangoni, A. / Liu, D. / Fast, W.
History
DepositionApr 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
B: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6374
Polymers67,2472
Non-polymers3902
Water61334
1
A: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8192
Polymers33,6231
Non-polymers1951
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8192
Polymers33,6231
Non-polymers1951
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.810, 46.850, 80.270
Angle α, β, γ (deg.)90.000, 109.150, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 / Dimethylarginine dimethylaminohydrolase 1 / DDAHI / Dimethylargininase-1


Mass: 33623.492 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDAH1, DDAH / Production host: Escherichia coli (E. coli) / References: UniProt: O94760, dimethylargininase
#2: Chemical ChemComp-NOU / (2S)-2-amino-4-[(pyridin-2-yl)amino]butanoic acid


Mass: 195.218 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H13N3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 34 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 36.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: Purified DDAH1 was concentrated to approximately 10 mg/mL using an Amicon-Ultra centrifugal filter device (10 kDa MWCO). The protein was crystallized at 25 C using the hanging drop method ...Details: Purified DDAH1 was concentrated to approximately 10 mg/mL using an Amicon-Ultra centrifugal filter device (10 kDa MWCO). The protein was crystallized at 25 C using the hanging drop method (Hampton Research, Aliso Viejo, CA) from 25 % (w/v) PEG6000, 0.1 M Tris-HCl, pH 8.2. Further optimization was done manually using a 1:1 well solution: DDAH1 stock solution ratio to improve crystal size and morphology. Crystals grew to their maximum size in 3 weeks and were harvested after approximately 25 days. To determine the structure of DDAH1 in complex with ligand, the crystals were transferred to a reservoir containing 20 uL of 20 mM of ligand in the crystallization mother liquor (25% PEG 6000, 0.1 M Tris-HCl, pH 8.2) and soaked for 30 min. Before data collection, crystals with good size and morphology were transferred into a cryoprotection solution (Well Solution supplemented with 25 % (v/v) glycerol) for 1 to 5 seconds using a the cryoloop (Hampton Research, Laguna Niguel, CA). Individual hDDAH1:ligand crystals were flash frozen in liquid nitrogen before use.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 0.9787 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jun 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.2→75.83 Å / Num. obs: 24478 / % possible obs: 91.8 % / Redundancy: 5.1 % / Biso Wilson estimate: 47.78 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.037 / Rrim(I) all: 0.086 / Net I/σ(I): 6.8 / Num. measured all: 123773 / Scaling rejects: 149
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) all% possible allRrim(I) all
2.2-2.273.21.08413480.3830.69959.8
9.07-75.834.90.0444170.9870.02399.20.05

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P8E

3p8e


Resolution: 2.2→62.56 Å / SU ML: 0.38 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 34.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2668 1205 4.93 %
Rwork0.2075 23243 -
obs0.2103 24448 91.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 158.68 Å2 / Biso mean: 71.5289 Å2 / Biso min: 28.8 Å2
Refinement stepCycle: final / Resolution: 2.2→62.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4234 0 0 34 4268
Biso mean---57.71 -
Num. residues----550
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2-2.290.4901920.37961670176260
2.29-2.390.3881110.34592046215774
2.39-2.520.39711230.29452541266490
2.52-2.680.32941530.288427782931100
2.68-2.880.34671670.280427972964100
2.88-3.170.34941390.249327992938100
3.17-3.630.29061420.217928442986100
3.63-4.580.24391320.168828442976100
4.58-62.560.1751460.155729243070100
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)
10.15050.50280.07971.78281.1271.664-0.17850.1521-0.34390.384-0.01930.21020.05340.0324-0.00040.4650.0271-0.01110.43180.0960.42212.4876-3.88046.1456
20.25770.25460.52340.73560.18610.9888-0.05390.0798-0.1114-0.08450.0106-0.0550.036-0.13910.00010.3940.02030.00690.36910.07030.52763.8969-6.3589-0.5174
32.27070.1813-0.17740.37220.25690.9402-0.2676-0.55850.06460.29370.14210.12880.01810.0559-0.0010.4670.0309-0.00340.4383-0.0380.43714.66710.28568.4882
41.14030.1920.25540.111-0.06040.0222-0.5765-0.61620.73421.10070.09590.1717-0.3191-0.4505-0.05680.65230.04070.01690.5248-0.09480.334912.67185.991713.5967
52.29871.11740.03331.10610.06121.4772-0.2166-0.12760.7222-0.07760.2466-0.3369-0.37770.18650.03010.4854-0.0314-0.09840.3988-0.1280.449621.9669.60443.5716
60.66490.1523-0.19880.77320.7950.8927-0.1491-0.27980.37-0.05660.4462-0.398-0.85710.996-0.00090.5333-0.1716-0.02850.5981-0.1760.72928.188312.80372.0454
70.82420.9786-0.27950.9611-0.59070.6781-0.34290.43060.558-0.03420.3906-0.1564-0.20960.15480.00010.4765-0.0769-0.05190.4452-0.02450.500721.09841.5161-9.6534
80.23160.5468-0.64350.6527-0.94511.4040.02610.74010.3907-0.63530.2842-0.8901-0.40210.66140.00030.6642-0.21140.09830.6929-0.10620.6628.71044.3333-14.1626
90.87050.6463-0.95241.56360.16451.7176-0.22830.2352-0.3619-0.24550.0219-0.22170.2778-0.137300.4687-0.02480.00920.4067-0.110.409618.8551-10.9818-8.7773
101.2695-0.1042-1.39241.0763-0.06411.5901-0.03790.1156-0.40910.06670.13790.0231-0.00670.17950.00010.343-0.0105-0.03710.3138-0.01980.410615.8873-7.0269-1.8458
110.0970.1166-0.45563.3905-1.18460.90620.007-0.51610.52361.48710.3781-0.6141-0.4028-0.21590.13731.11980.17070.03360.69220.10820.58611.26817.334-30.5834
120.4490.6415-0.74921.9921-1.33780.75580.08080.59690.2320.2965-0.0525-0.9578-0.4170.03880.00010.64780.0526-0.08810.6698-0.01580.93389.306310.3341-37.7325
132.51010.7660.24621.4841-0.0221.4749-0.3815-1.046-0.80211.21460.55070.3335-0.39770.0224-0.00010.82120.17160.08490.78610.24680.73290.18961.6346-28.4563
142.94870.1154-0.3080.26910.29380.8795-1.1839-1.1217-1.97491.79550.96981.2525-0.2267-0.53260.03631.15070.37230.34020.8970.57360.7817-4.7452-4.2334-25.7969
150.3743-0.1253-0.0350.07390.24650.7342-0.0930.9804-2.0461-0.05780.59752.2550.5037-1.33920.06140.5009-0.02290.23331.17610.18351.6084-10.6799-5.3546-39.6193
161.59760.3813-0.45670.105-0.20290.4229-0.12330.0538-2.71760.39180.2491.4810.3737-1.35910.59660.7254-0.0420.57981.00940.30261.789-14.8726-9.0018-34.3645
170.68620.6547-0.49780.5594-0.31420.40860.16320.9616-1.25-0.52260.2930.63430.0898-0.63070.00480.5857-0.0849-0.03311.00980.01470.9033-5.92870.6246-44.6028
181.0199-0.7858-0.39973.3285-2.13794.26860.06420.80010.1817-0.50750.36091.1027-0.1046-0.79090.01610.42920.035-0.01871.04720.20290.8793-11.22228.3268-45.7883
190.89421.36450.39672.12190.67770.39020.01470.68410.70380.31790.11260.0831-0.20370.0741-0.0010.59680.18550.15790.96180.35610.7683-5.528618.1101-45.7186
201.44420.80610.62511.47840.35230.2557-0.24380.0778-1.06410.72770.0875-0.163-0.0896-0.09180.01840.65520.09580.10920.60010.06040.4772-1.51666.165-35.0802
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 8 through 28 )A8 - 28
2X-RAY DIFFRACTION2chain 'A' and (resid 29 through 55 )A29 - 55
3X-RAY DIFFRACTION3chain 'A' and (resid 56 through 95 )A56 - 95
4X-RAY DIFFRACTION4chain 'A' and (resid 96 through 111 )A96 - 111
5X-RAY DIFFRACTION5chain 'A' and (resid 112 through 147 )A112 - 147
6X-RAY DIFFRACTION6chain 'A' and (resid 148 through 167 )A148 - 167
7X-RAY DIFFRACTION7chain 'A' and (resid 168 through 191 )A168 - 191
8X-RAY DIFFRACTION8chain 'A' and (resid 192 through 214 )A192 - 214
9X-RAY DIFFRACTION9chain 'A' and (resid 215 through 251 )A215 - 251
10X-RAY DIFFRACTION10chain 'A' and (resid 252 through 282 )A252 - 282
11X-RAY DIFFRACTION11chain 'B' and (resid 8 through 28 )B8 - 28
12X-RAY DIFFRACTION12chain 'B' and (resid 29 through 55 )B29 - 55
13X-RAY DIFFRACTION13chain 'B' and (resid 56 through 100 )B56 - 100
14X-RAY DIFFRACTION14chain 'B' and (resid 101 through 133 )B101 - 133
15X-RAY DIFFRACTION15chain 'B' and (resid 134 through 147 )B134 - 147
16X-RAY DIFFRACTION16chain 'B' and (resid 148 through 167 )B148 - 167
17X-RAY DIFFRACTION17chain 'B' and (resid 168 through 182 )B168 - 182
18X-RAY DIFFRACTION18chain 'B' and (resid 183 through 242 )B183 - 242
19X-RAY DIFFRACTION19chain 'B' and (resid 243 through 264 )B243 - 264
20X-RAY DIFFRACTION20chain 'B' and (resid 265 through 282 )B265 - 282

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