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- PDB-7ulx: Human DDAH1 soaked with its inhibitor N4-(4-chloropyridin-2-yl)-L... -

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Basic information

Entry
Database: PDB / ID: 7ulx
TitleHuman DDAH1 soaked with its inhibitor N4-(4-chloropyridin-2-yl)-L-asparagine
ComponentsN(G),N(G)-dimethylarginine dimethylaminohydrolase 1
KeywordsHYDROLASE / DDAH1 / Dimethylargininase / DDAH / inhibitor / N4-(4-chloropyridin-2-yl)-L-asparagine
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
N-(pyridin-2-yl)-L-asparagine / N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.707 Å
AuthorsZheng, Y. / Butrin, A. / 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

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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)67,6654
Polymers67,2472
Non-polymers4182
Water9,674537
1
A: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8332
Polymers33,6231
Non-polymers2091
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)33,8332
Polymers33,6231
Non-polymers2091
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.435, 47.590, 81.120
Angle α, β, γ (deg.)90.000, 109.010, 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-NQ6 / N-(pyridin-2-yl)-L-asparagine


Mass: 209.202 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H11N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 537 / 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: 1.99 Å3/Da / Density % sol: 38.28 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging 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 the ligand, the crystals were transferred to a reservoir containing 20 uL of 20 mM of the 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: 19-BM / Wavelength: 0.9787 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Mar 12, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.707→50 Å / Num. obs: 56084 / % possible obs: 96.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.04 / Rrim(I) all: 0.078 / Χ2: 0.9 / Net I/σ(I): 7.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.71-1.742.80.64225130.6240.420.7720.81388.5
1.74-1.7730.57327480.7230.370.6860.78294.5
1.77-1.813.30.57327990.7390.3580.680.84198.3
1.81-1.843.70.49328790.8710.2890.5740.81299.8
1.84-1.883.90.41628710.8880.2390.4810.85899.9
1.88-1.9340.3528750.930.2010.4050.903100
1.93-1.9740.27328640.9550.1550.3150.969100
1.97-2.0340.22628640.9620.1280.2610.961100
2.03-2.0940.18729220.9720.1060.2160.99599.8
2.09-2.1540.15628410.9790.0890.180.9999.9
2.15-2.2340.12128780.9890.0690.1390.97299.9
2.23-2.3240.10928850.9870.0620.1250.98799.9
2.32-2.4340.09129000.9920.0520.1050.96899.9
2.43-2.553.90.07628840.9940.0440.0880.91299.8
2.55-2.713.90.06828560.9930.0390.0790.90299.7
2.71-2.923.80.05729220.9950.0340.0670.81699.5
2.92-3.223.70.0528530.9950.030.0580.8298.6
3.22-3.683.50.04627640.9940.0290.0550.81294.4
3.68-4.643.30.04425080.9940.0280.0520.82185.5
4.64-503.30.04624580.9930.0290.0550.90481.2

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
iMOSFLMdata reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P8E
Resolution: 1.707→28.348 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 24.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2351 2322 4.9 %
Rwork0.1913 45024 -
obs0.1934 47346 81.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 89.82 Å2 / Biso mean: 27.7625 Å2 / Biso min: 3.01 Å2
Refinement stepCycle: final / Resolution: 1.707→28.348 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4236 0 0 537 4773
Biso mean---34.1 -
Num. residues----550
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.707-1.74160.3294660.22118837
1.7416-1.77950.2268740.2256147046
1.7795-1.82090.2357770.232179555
1.8209-1.86640.24491010.2323201363
1.8664-1.91690.28911110.2343224870
1.9169-1.97320.25341400.2196248477
1.9732-2.03690.26691490.2094273184
2.0369-2.10970.25151360.199297893
2.1097-2.19410.251620.1922319398
2.1941-2.2940.19561670.19383223100
2.294-2.41480.23811590.19453235100
2.4148-2.5660.26381810.19423207100
2.566-2.7640.2551540.20243255100
2.764-3.04190.24641730.2044322299
3.0419-3.48140.24111630.1815317197
3.4814-4.38350.20791740.1578285388
4.3835-28.3480.19521350.1696275882
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.5449-0.19290.11190.9368-0.13531.0734-0.01070.0275-0.04980.1333-0.02470.02310.00060.0242-0.00320.08130.0088-0.01670.0453-0.00030.121-0.7396-2.616444.2995
21.1526-0.0498-0.10690.98880.23850.62480.01160.10780.008-0.00940.00480.1347-0.0198-0.1601-0.01930.0857-0.0325-0.0040.0115-0.0030.1017-9.6213-5.476737.6674
30.7562-0.78440.33911.293-0.30250.6527-0.0689-0.1858-0.14330.33710.04460.00540.0902-0.12190.03340.11890.0133-0.02120.05580.01860.0941-3.3666-3.495747.4361
41.1030.273-0.11610.77220.21541.0184-0.0297-0.10670.04170.1620.0256-0.19680.02780.18120.01220.0515-0.0098-0.07170.06380.00130.06586.84327.162545.8988
51.5085-0.89770.76941.7564-1.17931.4111-0.0671-0.33740.09350.4150.08490.0112-0.0441-0.03470.09690.23990.0128-0.0590.139-0.0540.0727-0.47577.169751.9854
60.6644-0.0730.14840.7052-0.16810.6835-0.0661-0.1030.12840.1940.1199-0.1765-0.10260.1162-0.00480.12030.0033-0.04560.0728-0.0350.10787.607710.994746.2292
70.6579-0.177-0.04150.8190.19380.65230.06550.02810.1026-0.0630.0862-0.297-0.33490.21620.09960.1346-0.11690.00590.1242-0.05290.162712.868712.469437.9464
80.82930.2094-0.1231.19810.16841.0937-0.12830.1855-0.1193-0.2550.1392-0.3129-0.14510.26780.03870.083-0.04090.01780.1436-0.03710.115810.8109-0.508928.8184
90.42620.12480.24360.44420.38090.94870.00060.1872-0.1458-0.12160.0301-0.01650.2112-0.0295-0.04840.1892-0.0723-0.00130.2237-0.15760.07711.5644-11.282624.0872
101.24630.02140.130.79820.12830.818-0.05760.097-0.1305-0.00210.0677-0.16640.10340.05670.00790.06670.0074-0.0030.0565-0.01260.09652.6205-6.001636.5279
110.9202-0.27540.05181.10530.5650.78460.1005-0.1230.00490.45910.0359-0.002-0.0406-0.2247-0.08530.29290.01210.05020.27620.07670.2189-12.13318.71466.9591
121.55290.11360.17551.5394-0.4580.24720.07450.0032-0.08120.21310.0163-0.3059-0.11540.0536-0.07190.2271-0.0055-0.04890.20460.00810.2715-4.18512.11240.203
130.9252-0.69280.10061.3003-0.1760.71230.0396-0.24780.13910.42250.096-0.0297-0.08420.0567-0.0770.3677-0.0219-0.03620.28480.0620.1904-8.84748.67569.7362
140.66140.1495-0.120.6091-0.42410.79010.018-0.1259-0.0790.22560.07170.1868-0.1118-0.16440.06660.29190.03310.110.32050.15980.2897-19.5152-1.18.9122
150.5695-0.8608-0.70341.35151.12330.93570.0242-0.342-0.12120.58430.14210.12870.00690.0015-0.01180.54840.04170.03720.40250.12340.2714-11.6596-1.102714.2766
160.6136-0.0892-0.05840.51580.2350.74360.0439-0.1762-0.160.40250.08090.12520.025-0.07360.01930.34550.00420.09950.33470.15380.3165-20.2769-4.99079.1845
171.7695-0.3508-0.05941.33340.10741.18810.11730.1113-0.0077-0.19930.0830.09520.0892-0.1787-0.07680.2094-0.07770.00340.41210.0910.5-23.5341-3.9466-1.9023
180.48520.40850.01770.8675-0.44520.4066-0.08010.0348-0.38470.12510.10890.24920.1778-0.18140.05250.2788-0.09930.06640.37650.10350.4068-24.2532-3.9053-0.707
190.2780.0040.24171.89120.2621.16930.06560.2628-0.2686-0.12510.04480.10060.2988-0.137-0.00540.3227-0.1791-0.18770.59680.11450.5032-26.46981.7401-12.5913
201.47360.2535-0.09420.7949-0.05541.1291-0.01060.13660.0313-0.1610.09620.5071-0.0926-0.3238-0.02970.22050.0298-0.00720.40660.14520.3042-26.22810.988-5.7461
210.57340.1146-0.51810.1255-0.20660.94130.01520.11230.109-0.03930.06260.0987-0.105-0.0797-0.10020.21390.07730.16890.43610.27950.2308-17.764218.2462-9.6185
220.8697-0.0857-0.17210.73730.20860.56290.02250.05190.0550.23320.06550.1521-0.1097-0.173-0.03470.19610.05080.07830.28270.08460.1918-16.089512.2684-0.3269
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 76 )A56 - 76
4X-RAY DIFFRACTION4chain 'A' and (resid 77 through 95 )A77 - 95
5X-RAY DIFFRACTION5chain 'A' and (resid 96 through 111 )A96 - 111
6X-RAY DIFFRACTION6chain 'A' and (resid 112 through 133 )A112 - 133
7X-RAY DIFFRACTION7chain 'A' and (resid 134 through 167 )A134 - 167
8X-RAY DIFFRACTION8chain 'A' and (resid 168 through 236 )A168 - 236
9X-RAY DIFFRACTION9chain 'A' and (resid 237 through 251 )A237 - 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 56 )B29 - 56
13X-RAY DIFFRACTION13chain 'B' and (resid 57 through 76 )B57 - 76
14X-RAY DIFFRACTION14chain 'B' and (resid 77 through 95 )B77 - 95
15X-RAY DIFFRACTION15chain 'B' and (resid 96 through 111 )B96 - 111
16X-RAY DIFFRACTION16chain 'B' and (resid 112 through 133 )B112 - 133
17X-RAY DIFFRACTION17chain 'B' and (resid 134 through 147 )B134 - 147
18X-RAY DIFFRACTION18chain 'B' and (resid 148 through 182 )B148 - 182
19X-RAY DIFFRACTION19chain 'B' and (resid 183 through 204 )B183 - 204
20X-RAY DIFFRACTION20chain 'B' and (resid 205 through 230 )B205 - 230
21X-RAY DIFFRACTION21chain 'B' and (resid 231 through 251 )B231 - 251
22X-RAY DIFFRACTION22chain 'B' and (resid 252 through 282 )B252 - 282

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