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- PDB-6xju: Crystal Structure of KPT-8602 bound to CRM1 (E582K, 537-DLTVK-541... -

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Basic information

Entry
Database: PDB / ID: 6xju
TitleCrystal Structure of KPT-8602 bound to CRM1 (E582K, 537-DLTVK-541 to GLCEQ)
Components
  • Exportin-1
  • GTP-binding nuclear protein Ran
  • Ran-specific GTPase-activating protein 1
KeywordsPROTEIN TRANSPORT / Nuclear export / CRM1 / XPO1 / Exportin-1
Function / homology
Function and homology information


positive regulation of mitotic centrosome separation / RNA nuclear export complex / pre-miRNA export from nucleus / nuclear export signal receptor activity / snRNA import into nucleus / Transport of Mature mRNA derived from an Intron-Containing Transcript / cellular response to mineralocorticoid stimulus / Regulation of HSF1-mediated heat shock response / manchette / Regulation of cholesterol biosynthesis by SREBP (SREBF) ...positive regulation of mitotic centrosome separation / RNA nuclear export complex / pre-miRNA export from nucleus / nuclear export signal receptor activity / snRNA import into nucleus / Transport of Mature mRNA derived from an Intron-Containing Transcript / cellular response to mineralocorticoid stimulus / Regulation of HSF1-mediated heat shock response / manchette / Regulation of cholesterol biosynthesis by SREBP (SREBF) / SUMOylation of SUMOylation proteins / importin-alpha family protein binding / spindle pole body / protein localization to kinetochore / SUMOylation of RNA binding proteins / protein localization to nucleolus / U4 snRNA binding / Rev-mediated nuclear export of HIV RNA / nuclear export / Nuclear import of Rev protein / GTP metabolic process / NEP/NS2 Interacts with the Cellular Export Machinery / tRNA processing in the nucleus / RNA export from nucleus / SUMOylation of chromatin organization proteins / Postmitotic nuclear pore complex (NPC) reformation / MicroRNA (miRNA) biogenesis / nuclear import signal receptor activity / DNA metabolic process / dynein intermediate chain binding / NLS-bearing protein import into nucleus / MAPK6/MAPK4 signaling / mitotic sister chromatid segregation / spermatid development / ribosomal large subunit export from nucleus / sperm flagellum / U5 snRNA binding / ribosomal small subunit export from nucleus / U2 snRNA binding / U6 snRNA binding / mRNA export from nucleus / ribosomal subunit export from nucleus / nuclear pore / U1 snRNA binding / centriole / protein export from nucleus / viral process / GTPase activator activity / mitotic spindle organization / G protein activity / male germ cell nucleus / hippocampus development / Transcriptional regulation by small RNAs / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / recycling endosome / kinetochore / small GTPase binding / positive regulation of protein import into nucleus / G1/S transition of mitotic cell cycle / protein import into nucleus / GDP binding / melanosome / positive regulation of protein binding / nuclear envelope / mitotic cell cycle / midbody / actin cytoskeleton organization / ubiquitin-dependent protein catabolic process / cadherin binding / protein heterodimerization activity / protein domain specific binding / cell division / GTPase activity / chromatin binding / chromatin / nucleolus / GTP binding / perinuclear region of cytoplasm / magnesium ion binding / protein-containing complex / RNA binding / extracellular exosome / nucleoplasm / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
Ran-specific GTPase-activating protein 1, Ran-binding domain / Exportin-1, C-terminal / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / CRM1 C terminal / Chromosome region maintenance or exportin repeat / CRM1 / Exportin repeat 2 / CRM1 / Exportin repeat 3 / CRM1 C terminal ...Ran-specific GTPase-activating protein 1, Ran-binding domain / Exportin-1, C-terminal / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / CRM1 C terminal / Chromosome region maintenance or exportin repeat / CRM1 / Exportin repeat 2 / CRM1 / Exportin repeat 3 / CRM1 C terminal / Exportin-1/5 / Exportin-1/Importin-beta-like / Exportin 1-like protein / Ran binding protein RanBP1-like / Ran binding domain / RanBP1 domain / Ran binding domain type 1 profile. / Ran-binding domain / small GTPase Ran family profile. / Ran GTPase / Importin-beta N-terminal domain profile. / Importin-beta N-terminal domain / Importin-beta N-terminal domain / Importin-beta, N-terminal domain / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Armadillo-like helical / Small GTP-binding protein domain / PH-like domain superfamily / Armadillo-type fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-6L8 / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Exportin-1 / Ran-specific GTPase-activating protein 1 / GTP-binding nuclear protein Ran
Similarity search - Component
Biological speciesHomo sapiens (human)
Saccharomyces cerevisiae (brewer's yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.193 Å
AuthorsBaumhardt, J.M. / Chook, Y.M.
Funding support2items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)
Welch Foundation
CitationJournal: J Hematol Oncol / Year: 2021
Title: Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia.
Authors: Walker, J.S. / Hing, Z.A. / Harrington, B. / Baumhardt, J. / Ozer, H.G. / Lehman, A. / Giacopelli, B. / Beaver, L. / Williams, K. / Skinner, J.N. / Cempre, C.B. / Sun, Q. / Shacham, S. / ...Authors: Walker, J.S. / Hing, Z.A. / Harrington, B. / Baumhardt, J. / Ozer, H.G. / Lehman, A. / Giacopelli, B. / Beaver, L. / Williams, K. / Skinner, J.N. / Cempre, C.B. / Sun, Q. / Shacham, S. / Stromberg, B.R. / Summers, M.K. / Abruzzo, L.V. / Rassenti, L. / Kipps, T.J. / Parikh, S. / Kay, N.E. / Rogers, K.A. / Woyach, J.A. / Coppola, V. / Chook, Y.M. / Oakes, C. / Byrd, J.C. / Lapalombella, R.
History
DepositionJun 24, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GTP-binding nuclear protein Ran
B: Ran-specific GTPase-activating protein 1
C: Exportin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,1966
Polymers158,2203
Non-polymers9773
Water10,052558
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.965, 105.965, 305.398
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein GTP-binding nuclear protein Ran / Androgen receptor-associated protein 24 / GTPase Ran / Ras-like protein TC4 / Ras-related nuclear protein


Mass: 24456.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAN, ARA24, OK/SW-cl.81 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62826
#2: Protein Ran-specific GTPase-activating protein 1 / Chromosome stability protein 20 / Perinuclear array-localized protein / Ran-binding protein 1 / RANBP1


Mass: 16320.687 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: YRB1, CST20, HTN1, SFO1, YDR002W, YD8119.08 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P41920
#3: Protein Exportin-1 / Chromosome region maintenance protein 1 / Karyopherin-124


Mass: 117442.875 Da / Num. of mol.: 1 / Mutation: E582K, 537-DLTVK-541 to GLCEQ
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: CRM1, KAP124, XPO1, YGR218W, G8514 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P30822

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Non-polymers , 4 types, 561 molecules

#4: Chemical ChemComp-GNP / PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER


Mass: 522.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O13P3
Comment: GppNHp, GMPPNP, energy-carrying molecule analogue*YM
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-6L8 / (2R)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-2-(pyrimidin-5-yl)propanamide


Mass: 430.307 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H12F6N6O / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 558 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.71 Å3/Da / Density % sol: 54.58 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop
Details: 17% (weight/vol) PEG3350, 100 mM Bis-Tris (pH 6.4), 200 mM ammonium nitrate, and 10 mM Spermine HCl

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 1, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.193→40 Å / Num. obs: 135769 / % possible obs: 100 % / Redundancy: 15.8 % / Rmerge(I) obs: 0.152 / Rpim(I) all: 0.04 / Rrim(I) all: 0.157 / Χ2: 0.947 / Net I/σ(I): 4.9
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2
2.2-2.2415.97.42444130.7091.9057.6680.742
2.24-2.2815.41.90144260.8150.5061.9692.45
2.28-2.3216.11.52144060.7970.3891.5711.014
2.32-2.37161.24644470.8810.3191.2870.663
2.37-2.4216.11.06944340.920.2731.1040.664
2.42-2.4815.80.8844430.9460.2270.910.669
2.48-2.5415.50.85144190.9360.2240.8811.006
2.54-2.6115.20.61644510.9650.1620.6370.68
2.61-2.6913.90.54244380.9670.1480.5620.887
2.69-2.7716.50.41944460.9840.1060.4320.699
2.77-2.8716.50.33644900.9890.0850.3460.74
2.87-2.9916.50.25144370.9930.0630.2590.7
2.99-3.1216.30.19445060.9950.0490.20.721
3.12-3.2916.10.16644910.9960.0430.1720.938
3.29-3.4914.60.12245110.9970.0330.1270.975
3.49-3.7616.80.10545360.9970.0260.1081.183
3.76-4.1416.70.09145260.9980.0230.0941.232
4.14-4.7416.20.06645940.9980.0170.0680.91
4.74-5.9715.30.06346580.9980.0170.0660.831
5.97-4015.10.07249260.9970.020.0751.259

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HB2

4hb2


Resolution: 2.193→38.175 Å / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 26.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2254 3083 2.27 %
Rwork0.1993 132686 -
obs0.1999 135769 79.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 173.43 Å2 / Biso mean: 46.9256 Å2 / Biso min: 6.02 Å2
Refinement stepCycle: final / Resolution: 2.193→38.175 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10818 0 87 558 11463
Biso mean--30.09 40.23 -
Num. residues----1341
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00511346
X-RAY DIFFRACTIONf_angle_d0.62415406
X-RAY DIFFRACTIONf_chiral_restr0.041753
X-RAY DIFFRACTIONf_plane_restr0.0041964
X-RAY DIFFRACTIONf_dihedral_angle_d16.4466888
LS refinement shell

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

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.193-2.22680.3092610.3112259535
2.2268-2.26330.5855690.5537300039
2.2633-2.30230.3813860.3144371749
2.3023-2.34420.292930.2463392152
2.3442-2.38930.296910.2463394253
2.3893-2.4380.2608940.2362407554
2.438-2.4910.23021040.235434657
2.491-2.5490.25821170.245479963
2.549-2.61270.26971210.2198549473
2.6127-2.68330.32951400.2256614381
2.6833-2.76230.27841720.2259746299
2.7623-2.85140.23581840.22357582100
2.8514-2.95330.25871750.21387545100
2.9533-3.07150.29551780.22387563100
3.0715-3.21120.23261700.21247592100
3.2112-3.38040.23471700.19927537100
3.3804-3.5920.20441710.19377575100
3.592-3.86910.19961800.17927549100
3.8691-4.2580.17711720.15747571100
4.258-4.87310.15691830.14667549100
4.8731-6.13550.23011760.17927570100
6.1355-38.1750.19221760.19147559100
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)
10.03160.0251-0.04080.0606-0.08030.07150.06340.2146-0.0351-0.07210.1533-0.3162-0.1810.18250.01820.1896-0.07850.05860.3625-0.09710.341662.0388-3.93932.9015
20.0126-0.0085-0.00510.0357-0.03130.02080.03480.0054-0.05490.00850.0052-0.2611-0.03380.0357-0.0031-0.1455-0.0419-0.05210.3618-0.17290.498761.2884-15.771836.8367
30.0090.0106-0.00910.0171-0.02230.0072-0.04240.0549-0.0828-0.07660.0483-0.18930.07370.02870.00170.15450.0015-0.02180.3212-0.0490.282251.4338-18.554238.9197
40.08710.0066-0.10920.0719-0.00330.14570.06850.07210.04090.03860.11960.0045-0.1744-0.09750.0310.1771-0.0480.01960.3081-0.02010.228849.1965-3.695138.4975
50.00360.00090.0004-0.00020.00190.00690.0087-0.01590.0083-0.0060.0106-0.0344-0.01520.00150.00010.5091-0.17640.1280.7342-0.07520.490571.176521.6521.598
60.00190.0057-0.00350.002-0.00140.0028-0.02240.03430.0019-0.0417-0.063-0.01510.016-0.0262-00.4814-0.09870.1020.632-0.06060.398671.513610.19424.316
70.001-0.00250.00240.0019-0.00340.003-0.01020.0165-0.00870.02460.0360.01160.0078-0.0032-00.3672-0.08250.11770.4646-0.14810.535350.84683.487612.203
80.01230.0076-0.00140.02060.00070.0001-0.0232-0.0108-0.00290.0042-0.0349-0.0194-00.0092-00.9752-0.21890.00160.9253-0.22450.913361.40625.615832.879
90.0459-0.00070.05650.0023-0.00810.05420.0143-0.0665-0.14360.0022-0.12180.0526-0.32610.2858-0.00040.4597-0.16360.12340.3668-0.03690.394659.737115.33521.2417
100.0798-0.076-0.02150.280.12220.07050.1293-0.0014-0.1183-0.2277-0.04030.0801-0.43850.23390.00490.5378-0.19950.14470.3876-0.03580.392460.066217.909712.4067
110.21780.03610.05270.5710.06960.2137-0.0723-0.0138-0.10840.74330.2366-0.45280.50530.27120.32490.10030.1634-0.24740.3873-0.11320.498363.5533-27.510752.9104
120.3235-0.31270.03520.29250.28520.7550.05830.04370.01130.0681-0.0164-0.0123-0.11590.02050.08110.1645-0.03920.00520.2391-0.01390.149628.9449-1.492250.6377
130.27190.00510.15030.2489-0.00120.58310.07580.108-0.0247-0.18670.01540.022-0.3737-0.18080.04610.3260.05660.0380.26950.0490.192325.87533.44247.1259
140.3689-0.18650.05320.1272-0.14160.28430.07120.0477-0.1748-0.09090.04050.0847-0.00330.0550.00290.22490.0101-0.0150.2489-0.05010.287744.147-35.325414.6729
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 9 through 66 )A9 - 66
2X-RAY DIFFRACTION2chain 'A' and (resid 67 through 91 )A67 - 91
3X-RAY DIFFRACTION3chain 'A' and (resid 92 through 111 )A92 - 111
4X-RAY DIFFRACTION4chain 'A' and (resid 112 through 179 )A112 - 179
5X-RAY DIFFRACTION5chain 'A' and (resid 180 through 189 )A180 - 189
6X-RAY DIFFRACTION6chain 'A' and (resid 190 through 206 )A190 - 206
7X-RAY DIFFRACTION7chain 'A' and (resid 207 through 216 )A207 - 216
8X-RAY DIFFRACTION8chain 'B' and (resid 78 through 82 )B78 - 82
9X-RAY DIFFRACTION9chain 'B' and (resid 83 through 139 )B83 - 139
10X-RAY DIFFRACTION10chain 'B' and (resid 140 through 200 )B140 - 200
11X-RAY DIFFRACTION11chain 'C' and (resid -1 through 245 )C-1 - 245
12X-RAY DIFFRACTION12chain 'C' and (resid 246 through 541 )C246 - 541
13X-RAY DIFFRACTION13chain 'C' and (resid 542 through 808 )C542 - 808
14X-RAY DIFFRACTION14chain 'C' and (resid 809 through 1052 )C809 - 1052

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