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- PDB-7ulv: Human DDAH1 soaked with its inactivator S-((4-chloropyridin-2-yl)... -

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Basic information

Entry
Database: PDB / ID: 7ulv
TitleHuman DDAH1 soaked with its inactivator S-((4-chloropyridin-2-yl)methyl)-L-cysteine
ComponentsN(G),N(G)-dimethylarginine dimethylaminohydrolase 1
KeywordsHYDROLASE / DDAH1 / Dimethylargininase / DDAH / inactivator / S-((4-chloropyridin-2-yl)methyl)-L-cysteine
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 / amino acid binding / catalytic activity / 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 / amino acid binding / catalytic activity / nitric oxide mediated signal transduction / L-arginine catabolic process / eNOS activation / nitric oxide metabolic 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
S-[(pyridin-2-yl)methyl]-L-cysteine / N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.37 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
Revision 1.1Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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
C: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
D: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
E: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
F: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,01512
Polymers201,7416
Non-polymers1,2746
Water9,170509
1
A: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8362
Polymers33,6231
Non-polymers2121
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)33,8362
Polymers33,6231
Non-polymers2121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8362
Polymers33,6231
Non-polymers2121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8362
Polymers33,6231
Non-polymers2121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8362
Polymers33,6231
Non-polymers2121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8362
Polymers33,6231
Non-polymers2121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.404, 220.991, 73.645
Angle α, β, γ (deg.)90.000, 91.080, 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.: 6
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-NO6 / S-[(pyridin-2-yl)methyl]-L-cysteine


Mass: 212.269 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C9H12N2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 509 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 1.87 Å3/Da / Density % sol: 34.27 %
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 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: 21-ID-D / Wavelength: 0.97872 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Nov 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
Reflection twinOperator: h,-k,-l / Fraction: 0.18
ReflectionResolution: 2.37→73.66 Å / Num. obs: 59571 / % possible obs: 99.1 % / Redundancy: 4.3 % / Rpim(I) all: 0.062 / Rrim(I) all: 0.128 / Net I/σ(I): 8 / Num. measured all: 256173
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Mean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) all% possible all
2.37-2.414.33.51213128200.4060.83694.1
6.42-73.74.2131275630570.0360.073100

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Processing

Software
NameVersionClassification
xia2data scaling
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
xia2data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P8E

3p8e


Resolution: 2.37→73.63 Å / Cross valid method: THROUGHOUT / σ(F): 1.68 / Phase error: 36.67 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2692 2926 4.99 %
Rwork0.237 56622 -
obs0.2418 59548 99.02 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 99.33 Å2 / Biso mean: 45.4034 Å2 / Biso min: 15.98 Å2
Refinement stepCycle: final / Resolution: 2.37→73.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12606 0 0 509 13115
Biso mean---41.95 -
Num. residues----1632
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.37-2.410.37461300.35712689281990
2.41-2.450.40211320.34782875300794
2.45-2.50.38241500.33982773292394
2.5-2.550.37431570.33692821297894
2.55-2.60.3391520.33072840299294
2.6-2.670.35551820.32752763294593
2.67-2.730.33081550.32642836299193
2.73-2.810.33911360.322797293395
2.81-2.890.29621540.31272847300194
2.89-2.980.34171170.30382844296196
2.98-3.090.29181690.27912860302993
3.09-3.210.30421330.26532801293495
3.21-3.360.32471560.25422848300494
3.36-3.540.24031340.23212853298795
3.54-3.760.24391330.22322853298695
3.76-4.050.23541380.20682845298395
4.05-4.450.23621570.18852843300094
4.45-5.10.21371390.17982897303695
5.1-6.420.22631520.20942845299795
6.42-73.630.23261500.17292892304295
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)
10.14690.03840.2280.58870.22871.16110.0137-0.03360.02870.03870.03440.0354-0.054-0.04610.00710.38220.0455-0.05090.71230.07760.1207-4.7419-18.74811.1232
20.10260.0328-0.10430.3331-0.10460.78310.0134-0.01210.03510.2606-0.0097-0.0051-0.1615-0.02970.04910.4690.0493-0.07780.85330.0181-0.01637.4928-17.103412.5068
30.35070.01440.55820.82710.25871.6307-0.0052-0.1251-0.01230.2153-0.0152-0.01430.1205-0.02850.01820.44110.0302-0.06310.730.01730.12361.2117-34.734314.5211
40.34030.44030.0471.27740.32331.3324-0.0129-0.013-0.00350.0570.01750.01430.1014-0.02360.00810.3890.0530.0220.68790.02960.0347-8.2919-28.93628.1396
50.43660.11140.05590.71830.50561.4908-0.03460.0018-0.0365-0.0355-0.0047-0.00510.12980.0698-0.02190.31290.0798-0.01430.75720.04230.021717.6969-25.579-16.0875
60.43660.62170.80361.15921.43031.954-0.04720.1211-0.0498-0.2071-0.0083-0.0110.29550.02260.05270.46640.08190.03660.74780.00830.109427.8653-33.7594-25.3213
70.2131-0.0707-0.2220.3826-0.04250.8819-0.00990.0187-0.0279-0.03950.0265-0.08730.11780.3504-0.00150.33450.09630.06120.9487-0.03210.149835.8054-23.7804-31.0102
81.4977-1.2251-0.11881.7394-1.30152.6619-0.0297-0.0280.04580.08070.0251-0.1638-0.09050.46170.01440.24160.0190.02650.8350.03240.188529.2134-13.7873-24.9681
90.35890.1003-0.19120.15230.1040.4138-0.03550.0893-0.0179-0.12680.0294-0.1108-0.04980.4017-0.00180.3898-0.05830.00430.89790.07730.187430.7532-7.3797-32.3878
100.03950.0334-0.23070.76160.3631.8228-0.00750.1660.0173-0.1859-0.00520.03290.010.13520.00650.35750.0115-0.08750.82370.03990.194520.1035-12.3114-32.8103
110.2717-0.08160.22421.87230.35311.6259-0.04330.06460.0147-0.30750.07740.0763-0.0937-0.0023-0.02760.29710.0392-0.04270.71050.06390.059915.8136-14.0313-23.7402
120.89690.09090.89080.85880.0590.8916-0.0605-0.22230.09790.05710.00950.1049-0.07-0.35760.0660.47480.0565-0.12440.82670.00670.15352.936822.5006-6.7268
130.33260.07750.22770.41510.15440.1826-0.08110.12080.1477-0.2793-0.00760.1287-0.1391-0.13420.15280.59810.0283-0.23650.89160.06190.2466-9.302817.9229-16.5751
140.17270.22940.37191.21690.4711.1878-0.0190.1079-0.0663-0.130.02030.02980.1025-0.24320.01170.4788-0.0139-0.00870.7910.03210.16892.3533.3022-14.293
150.8878-0.6410.52531.1659-0.11972.3752-0.0985-0.1898-0.05-0.06040.09720.06190.1275-0.0976-0.02460.39840.0362-0.00860.70190.10880.148410.654410.977-8.4181
160.5314-0.03290.02210.97460.13161.312-0.02250.03520.01480.2391-0.07350.043-0.00060.11320.00550.36720.05010.09530.7307-0.02040.10684.3012-53.8641-1.7581
171.5691-0.3951-0.07042.09670.05565.32450.01710.30510.1147-0.3575-0.0411-0.1294-0.24130.45840.05460.42730.0371-0.07030.68180.00470.1306-8.703-51.4217-10.4108
180.05020.0870.13820.17340.17690.86640.09560.1127-0.0238-0.06240.01080.03150.0526-0.11810.00890.41980.0306-0.13041.0895-0.05260.1696-7.1687-60.2876-16.3443
190.4279-0.36030.13080.8307-0.14491.87860.01660.2461-0.0427-0.3301-0.0365-0.09470.10230.15160.04030.38960.02350.02130.887-0.06430.10679.1564-64.5419-12.5019
200.6577-0.16720.06441.1015-0.57362.0169-0.00790.0530.0020.1701-0.00860.00240.1178-0.06780.00250.4395-0.0348-0.00840.7730.01070.110428.3986-64.901914.8576
210.3122-0.42920.09520.7704-0.32630.86740.0843-0.0231-0.04910.0272-0.00880.01610.29450.0099-0.04010.5045-0.1102-0.02520.72340.01560.119316.9242-70.663522.6886
221.2348-0.0998-1.46561.1734-0.59192.8662-0.01990.0213-0.0440.26060.16190.23770.1786-0.6349-0.12430.5273-0.10530.06110.80580.06480.206712.4136-63.42631.0047
230.744-0.2427-0.16581.29620.12351.77180.108-0.1844-0.04360.34590.0129-0.0125-0.07450.0538-0.08530.6373-0.0372-0.03690.8759-0.02540.123628.0677-52.579827.7794
240.27640.0791-0.05040.50160.01861.5067-0.03980.11210.0298-0.25440.07480.03-0.2805-0.0919-0.07130.58150.00570.05971.07020.04890.220930.718812.747413.6862
250.9011-0.3070.51661.9203-0.10253.32070.1240.1241-0.0507-0.1799-0.112-0.09150.45230.3962-0.01690.50210.0092-0.0690.7911-0.01070.109421.79872.171819.5567
260.11180.0206-0.10620.7723-0.48591.66140.00010.07020.01460.0217-0.05560.0289-0.1836-0.08760.00090.44960.0478-0.02360.79750.05930.075218.181815.265331.2169
270.64430.026-1.13411.09090.19332.26390.1668-0.02150.0860.0107-0.2336-0.1654-0.21020.43220.04930.4579-0.04730.04911.08660.15730.247731.665921.727124.0743
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 54 )A9 - 54
2X-RAY DIFFRACTION2chain 'A' and (resid 55 through 167 )A55 - 167
3X-RAY DIFFRACTION3chain 'A' and (resid 168 through 230 )A168 - 230
4X-RAY DIFFRACTION4chain 'A' and (resid 231 through 282 )A231 - 282
5X-RAY DIFFRACTION5chain 'B' and (resid 9 through 77 )B9 - 77
6X-RAY DIFFRACTION6chain 'B' and (resid 78 through 118 )B78 - 118
7X-RAY DIFFRACTION7chain 'B' and (resid 119 through 167 )B119 - 167
8X-RAY DIFFRACTION8chain 'B' and (resid 168 through 182 )B168 - 182
9X-RAY DIFFRACTION9chain 'B' and (resid 183 through 204 )B183 - 204
10X-RAY DIFFRACTION10chain 'B' and (resid 205 through 230 )B205 - 230
11X-RAY DIFFRACTION11chain 'B' and (resid 231 through 282 )B231 - 282
12X-RAY DIFFRACTION12chain 'C' and (resid 9 through 95 )C9 - 95
13X-RAY DIFFRACTION13chain 'C' and (resid 96 through 167 )C96 - 167
14X-RAY DIFFRACTION14chain 'C' and (resid 168 through 230 )C168 - 230
15X-RAY DIFFRACTION15chain 'C' and (resid 231 through 282 )C231 - 282
16X-RAY DIFFRACTION16chain 'D' and (resid 9 through 80 )D9 - 80
17X-RAY DIFFRACTION17chain 'D' and (resid 81 through 101 )D81 - 101
18X-RAY DIFFRACTION18chain 'D' and (resid 102 through 204 )D102 - 204
19X-RAY DIFFRACTION19chain 'D' and (resid 205 through 282 )D205 - 282
20X-RAY DIFFRACTION20chain 'E' and (resid 9 through 76 )E9 - 76
21X-RAY DIFFRACTION21chain 'E' and (resid 77 through 111 )E77 - 111
22X-RAY DIFFRACTION22chain 'E' and (resid 112 through 167 )E112 - 167
23X-RAY DIFFRACTION23chain 'E' and (resid 168 through 282 )E168 - 282
24X-RAY DIFFRACTION24chain 'F' and (resid 9 through 71 )F9 - 71
25X-RAY DIFFRACTION25chain 'F' and (resid 72 through 118 )F72 - 118
26X-RAY DIFFRACTION26chain 'F' and (resid 119 through 230 )F119 - 230
27X-RAY DIFFRACTION27chain 'F' and (resid 231 through 282 )F231 - 282

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