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- PDB-7pjf: Inhibiting parasite proliferation using a rationally designed ant... -

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Basic information

Entry
Database: PDB / ID: 7pjf
TitleInhibiting parasite proliferation using a rationally designed anti-tubulin agent
Components
  • Designed ankyrin repeat protein (DARPIN) D1
  • Tubulin alpha-1B chain
  • Tubulin beta-3 chain
KeywordsSTRUCTURAL PROTEIN / Tubulin / Microtubules / Protozoa / Apicomplexa
Function / homology
Function and homology information


netrin receptor binding / Post-chaperonin tubulin folding pathway / dorsal root ganglion development / Cilium Assembly / cytoskeleton-dependent intracellular transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / Intraflagellar transport / Sealing of the nuclear envelope (NE) by ESCRT-III / Formation of tubulin folding intermediates by CCT/TriC ...netrin receptor binding / Post-chaperonin tubulin folding pathway / dorsal root ganglion development / Cilium Assembly / cytoskeleton-dependent intracellular transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / Intraflagellar transport / Sealing of the nuclear envelope (NE) by ESCRT-III / Formation of tubulin folding intermediates by CCT/TriC / Gap junction assembly / Prefoldin mediated transfer of substrate to CCT/TriC / Kinesins / COPI-independent Golgi-to-ER retrograde traffic / Assembly and cell surface presentation of NMDA receptors / COPI-dependent Golgi-to-ER retrograde traffic / Recycling pathway of L1 / RHOH GTPase cycle / RHO GTPases activate IQGAPs / microtubule-based process / Hedgehog 'off' state / Activation of AMPK downstream of NMDARs / intercellular bridge / COPI-mediated anterograde transport / cytoplasmic microtubule / peptide binding / Mitotic Prometaphase / MHC class II antigen presentation / EML4 and NUDC in mitotic spindle formation / cellular response to interleukin-4 / Recruitment of NuMA to mitotic centrosomes / axon guidance / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Resolution of Sister Chromatid Cohesion / cell periphery / Translocation of SLC2A4 (GLUT4) to the plasma membrane / filopodium / RHO GTPases Activate Formins / PKR-mediated signaling / structural constituent of cytoskeleton / microtubule cytoskeleton organization / HCMV Early Events / Aggrephagy / The role of GTSE1 in G2/M progression after G2 checkpoint / mitotic spindle / Separation of Sister Chromatids / mitotic cell cycle / lamellipodium / double-stranded RNA binding / microtubule cytoskeleton / growth cone / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / cilium / axon / cell division / neuronal cell body / GTPase activity / ubiquitin protein ligase binding / dendrite / GTP binding / structural molecule activity / extracellular exosome / metal ion binding / nucleus / cytoplasm
Similarity search - Function
Helix hairpin bin / Tubulin/FtsZ, C-terminal domain / Tubulin/FtsZ, GTPase domain / 60s Ribosomal Protein L30; Chain: A; / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal ...Helix hairpin bin / Tubulin/FtsZ, C-terminal domain / Tubulin/FtsZ, GTPase domain / 60s Ribosomal Protein L30; Chain: A; / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain / Tubulin/FtsZ-like, C-terminal domain / Tubulin/FtsZ, C-terminal / Tubulin/FtsZ, 2-layer sandwich domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, GTPase domain superfamily / Helix Hairpins / Rossmann fold / 2-Layer Sandwich / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-TRIPHOSPHATE / Tubulin alpha-1B chain / Tubulin beta-3 chain
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.862 Å
AuthorsSharma, A. / Gaillard, N. / Ehrhard, V.A. / Steinmetz, M.O.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Novartis FreeNovation Switzerland
CitationJournal: Embo Mol Med / Year: 2021
Title: Inhibiting parasite proliferation using a rationally designed anti-tubulin agent.
Authors: Gaillard, N. / Sharma, A. / Abbaali, I. / Liu, T. / Shilliday, F. / Cook, A.D. / Ehrhard, V. / Bangera, M. / Roberts, A.J. / Moores, C.A. / Morrissette, N. / Steinmetz, M.O.
History
DepositionAug 24, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 3, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 17, 2021Group: Data collection / Database references
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tubulin alpha-1B chain
B: Tubulin beta-3 chain
F: Designed ankyrin repeat protein (DARPIN) D1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,4447
Polymers117,3493
Non-polymers1,0954
Water7,891438
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6360 Å2
ΔGint-48 kcal/mol
Surface area35680 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.784, 91.312, 82.657
Angle α, β, γ (deg.)90.000, 97.550, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 3 types, 3 molecules ABF

#1: Protein Tubulin alpha-1B chain / Alpha-tubulin ubiquitous / Tubulin K-alpha-1 / Tubulin alpha-ubiquitous chain


Mass: 50204.445 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TUBA1B / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P68363
#2: Protein Tubulin beta-3 chain / Tubulin beta-4 chain / Tubulin beta-III


Mass: 50481.520 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TUBB3, TUBB4 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13509
#3: Protein Designed ankyrin repeat protein (DARPIN) D1


Mass: 16662.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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Non-polymers , 3 types, 442 molecules

#4: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 438 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.35 Å3/Da / Density % sol: 47.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 5.5
Details: 100 mM Bis-TrisMethane, pH 5.5, supplemented with 200 mM ammonium sulfate and 25% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 31, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.862→45.66 Å / Num. obs: 90758 / % possible obs: 99.8 % / Redundancy: 6.8 % / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.0701 / Rpim(I) all: 0.02872 / Rrim(I) all: 0.07585 / Net I/σ(I): 19.16
Reflection shellResolution: 1.862→1.929 Å / Redundancy: 6.7 % / Rmerge(I) obs: 1.22 / Mean I/σ(I) obs: 1.75 / Num. unique obs: 8956 / CC1/2: 0.782 / CC star: 0.937 / Rpim(I) all: 0.5035 / % possible all: 98.65

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DRX

4drx


Resolution: 1.862→45.66 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 1.26 / Phase error: 25.2 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2185 8916 5 %
Rwork0.1837 169423 -
obs0.1855 90707 99.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 141.37 Å2 / Biso mean: 39.8915 Å2 / Biso min: 17.34 Å2
Refinement stepCycle: final / Resolution: 1.862→45.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7728 0 66 438 8232
Biso mean--27.33 43.97 -
Num. residues----1002
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.8622-1.88340.39742840.3541539796
1.8834-1.90550.3642940.33785619100
1.9055-1.92880.37343010.31315736100
1.9288-1.95320.3352950.30195611100
1.9532-1.97890.32782920.28555616100
1.9789-2.0060.2932950.2655665100
2.006-2.03460.29562970.25775661100
2.0346-2.0650.28833000.24685673100
2.065-2.09730.28222970.23665649100
2.0973-2.13170.27453010.22565657100
2.1317-2.16840.25153010.21515707100
2.1684-2.20790.2822960.21025577100
2.2079-2.25030.23243000.20155681100
2.2503-2.29630.23723010.19545706100
2.2963-2.34620.2232900.19545628100
2.3462-2.40080.23782990.18635671100
2.4008-2.46080.22493040.18145694100
2.4608-2.52730.22342940.1865622100
2.5273-2.60170.22782960.18515685100
2.6017-2.68570.21532980.18145641100
2.6857-2.78160.21143000.18385652100
2.7816-2.8930.23573000.18935617100
2.893-3.02470.24373000.18985695100
3.0247-3.18410.21272980.18845711100
3.1841-3.38350.22632960.18545615100
3.3835-3.64470.2532960.18195650100
3.6447-4.01130.16722950.14935609100
4.0113-4.59140.17193000.13095692100
4.5914-5.78330.17582970.1436563199
5.7833-45.660.15262990.1585655100
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)
10.19960.16580.15670.52380.02910.99640.0479-0.15740.0246-0.0477-0.0632-0.09640.25340.7673-0.0020.2750.06180.01380.45340.00640.2156197.450316.924510.1138
20.5207-0.05460.38390.858-0.57510.96210.0778-0.273-0.08060.1593-0.10170.02650.01430.25660.00020.2852-0.0568-0.01340.3001-0.00970.2067188.973321.460924.2216
30.2674-0.3032-0.14570.6859-0.24831.6355-0.02440.0458-0.01820.0090.04250.0237-0.25430.181900.2952-0.07370.02860.2294-0.04270.2326185.050529.656915.1779
40.74880.1805-0.49430.0997-0.50421.7633-0.01870.2708-0.03960.00850.06150.0980.0666-0.1277-0.00090.2555-0.04570.01540.1961-0.06070.2365178.34822.54566.8139
50.8623-0.1897-0.91890.5356-0.60151.81170.0940.12410.1294-0.06240.05190.0629-0.48890.2680.00130.3503-0.06550.03590.315-0.05770.2819187.230529.4345-1.9865
6-0.0002-0.03550.04620.40680.35030.68890.1730.3259-0.07450.0373-0.08880.1462-0.2857-0.10.00470.29780.0063-0.01160.34030.00780.2554180.059926.7117-9.4404
71.3774-0.10350.11780.35370.40330.77140.31540.72730.3406-0.1274-0.3280.1553-0.70130.02950.00120.50050.07830.00850.34080.05170.3675183.044533.9806-16.4179
80.69470.2058-0.2904-0.0868-0.02711.2695-0.06230.1734-0.21850.0104-0.00520.0875-0.0518-0.0079-0.00040.2507-0.0430.02840.1860.00060.2391178.656725.13080.684
91.2652-0.22230.29811.0243-0.10160.11940.2325-0.43550.39140.06610.01860.0339-0.6181-0.1770.30660.45170.0550.12170.0614-0.03960.3347169.238738.773417.5951
102.1345-0.40980.27711.52860.03840.89610.0662-0.4417-0.11040.04060.0252-0.35860.23010.1922-0.00250.25350.0315-0.07140.32760.05310.4098166.064.808645.9568
111.47360.3373-0.27520.94610.18281.34150.0539-0.1974-0.0459-0.01150.0168-0.14040.02710.0171-0.00050.17380.0128-0.03390.17220.00850.2727153.55412.50440.6761
121.07230.25480.00430.5636-0.36831.75670.04430.2123-0.1441-0.29550.0215-0.11820.2016-0.1546-00.31170.01640.02540.2667-0.02830.3279155.497710.639325.1767
130.29110.18650.07380.3236-0.00780.4353-0.13740.6114-0.3584-0.28870.1303-0.07440.3388-0.3535-0.0010.45320.03090.07080.4835-0.13240.4002158.10369.613714.0395
141.13390.4308-0.11720.2806-0.22721.0990.05150.2296-0.0197-0.08740.0012-0.15920.1434-0.12320.00130.22990.01520.00650.1896-0.00710.2507150.379115.956527.4118
151.8572-0.248-0.2530.3994-0.32130.27070.3139-0.13880.57730.10080.0109-0.01-0.48220.09790.01110.3007-0.02180.05430.24750.00590.3765145.420727.830442.7709
160.5730.0007-0.23420.1266-0.0590.6260.2584-0.39650.10740.1191-0.0183-0.593-0.47990.67440.03090.3038-0.048-0.05450.64350.07230.267128.290821.465469.9445
170.2806-0.2669-0.17320.49190.34290.4411-0.0364-0.9282-0.10810.15420.0537-0.08340.09190.39070.0190.23390.0090.01090.51830.07920.2306124.893918.769666.7843
181.8494-0.04650.5630.26060.0580.1921-0.4647-0.981-0.482-0.00930.55180.53050.4821-0.5227-0.06210.2677-0.02730.02320.42530.17810.2977119.407311.337264.0838
190.0577-0.1067-0.05280.18990.06670.15620.0325-0.29430.22030.12770.0476-0.0511-0.0289-0.1221-0.00010.23820.0172-0.01250.29640.01890.2374120.429724.839355.5946
200.117-0.04260.08130.20270.06190.1145-0.1108-0.3245-0.31760.19090.0217-0.02630.24850.0218-0.00020.2489-0.01750.00280.24740.04260.2423123.444312.812952.1526
210.681-0.11450.42090.26370.00530.2818-0.00520.0607-0.0606-0.03240.0666-0.0011-0.0358-0.27080.00010.23690.0227-0.00330.26730.01680.2209123.82620.053345.2213
220.24610.06360.04670.16060.07250.0265-0.0617-0.4563-0.9343-0.41780.05310.16770.3112-0.102-0.00820.249-0.0377-0.00820.2666-0.01970.3514121.70849.216242.4514
230.3560.2554-0.06820.2833-0.09030.423-0.11750.158-0.1196-0.4902-0.2183-0.1592-0.2227-0.47410.00360.31240.0297-0.01040.33110.05090.2576121.960423.590936.0833
240.41220.16710.32021.20140.57090.46580.11210.7618-0.2549-0.6555-0.0863-0.3506-0.14920.28480.01180.3568-0.0003-0.0420.3822-0.03370.2856128.417813.562232.1411
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 2 through 64 )A2 - 64
2X-RAY DIFFRACTION2chain 'A' and (resid 65 through 128 )A65 - 128
3X-RAY DIFFRACTION3chain 'A' and (resid 129 through 180 )A129 - 180
4X-RAY DIFFRACTION4chain 'A' and (resid 181 through 243 )A181 - 243
5X-RAY DIFFRACTION5chain 'A' and (resid 244 through 287 )A244 - 287
6X-RAY DIFFRACTION6chain 'A' and (resid 288 through 324 )A288 - 324
7X-RAY DIFFRACTION7chain 'A' and (resid 325 through 351 )A325 - 351
8X-RAY DIFFRACTION8chain 'A' and (resid 352 through 401 )A352 - 401
9X-RAY DIFFRACTION9chain 'A' and (resid 402 through 436 )A402 - 436
10X-RAY DIFFRACTION10chain 'B' and (resid 1 through 128 )B1 - 128
11X-RAY DIFFRACTION11chain 'B' and (resid 129 through 238 )B129 - 238
12X-RAY DIFFRACTION12chain 'B' and (resid 239 through 311 )B239 - 311
13X-RAY DIFFRACTION13chain 'B' and (resid 312 through 338 )B312 - 338
14X-RAY DIFFRACTION14chain 'B' and (resid 339 through 401 )B339 - 401
15X-RAY DIFFRACTION15chain 'B' and (resid 402 through 440 )B402 - 440
16X-RAY DIFFRACTION16chain 'F' and (resid 13 through 24 )F13 - 24
17X-RAY DIFFRACTION17chain 'F' and (resid 25 through 59 )F25 - 59
18X-RAY DIFFRACTION18chain 'F' and (resid 60 through 69 )F60 - 69
19X-RAY DIFFRACTION19chain 'F' and (resid 70 through 82 )F70 - 82
20X-RAY DIFFRACTION20chain 'F' and (resid 83 through 101 )F83 - 101
21X-RAY DIFFRACTION21chain 'F' and (resid 102 through 125 )F102 - 125
22X-RAY DIFFRACTION22chain 'F' and (resid 126 through 135 )F126 - 135
23X-RAY DIFFRACTION23chain 'F' and (resid 136 through 148 )F136 - 148
24X-RAY DIFFRACTION24chain 'F' and (resid 149 through 167 )F149 - 167

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