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- PDB-4haz: Crystal structure of CRM1 inhibitor Leptomycin B in complex with ... -

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Basic information

Entry
Database: PDB / ID: 4haz
TitleCrystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(R543S,K548E,K579Q)-Ran-RanBP1
Components
  • Exportin-1
  • GTP-binding nuclear protein Ran
  • Ran-specific GTPase-activating protein 1
KeywordsPROTEIN TRANSPORT/ANTIBIOTIC / HEAT repeat / nuclear export / Ran-RanBP1 / LMB / leptomycin B / PROTEIN TRANSPORT-ANTIBIOTIC complex
Function / homology
Function and homology information


tRNA re-export from nucleus / Transport of Mature mRNA derived from an Intron-Containing Transcript / pre-miRNA export from nucleus / RNA nuclear export complex / snRNA import into nucleus / Regulation of HSF1-mediated heat shock response / nuclear export signal receptor activity / Transcriptional and post-translational regulation of MITF-M expression and activity / manchette / cellular response to mineralocorticoid stimulus ...tRNA re-export from nucleus / Transport of Mature mRNA derived from an Intron-Containing Transcript / pre-miRNA export from nucleus / RNA nuclear export complex / snRNA import into nucleus / Regulation of HSF1-mediated heat shock response / nuclear export signal receptor activity / Transcriptional and post-translational regulation of MITF-M expression and activity / manchette / cellular response to mineralocorticoid stimulus / Regulation of cholesterol biosynthesis by SREBP (SREBF) / tRNA export from nucleus / importin-alpha family protein binding / SUMOylation of SUMOylation proteins / protein localization to kinetochore / spindle pole body / Rev-mediated nuclear export of HIV RNA / Nuclear import of Rev protein / U4 snRNA binding / nuclear export / SUMOylation of RNA binding proteins / protein localization to nucleolus / NEP/NS2 Interacts with the Cellular Export Machinery / RNA export from nucleus / GTP metabolic process / tRNA processing in the nucleus / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of chromatin organization proteins / nuclear import signal receptor activity / MicroRNA (miRNA) biogenesis / DNA metabolic process / MAPK6/MAPK4 signaling / dynein intermediate chain binding / mitotic sister chromatid segregation / ribosomal large subunit export from nucleus / U5 snRNA binding / spermatid development / viral process / U2 snRNA binding / U6 snRNA binding / positive regulation of protein binding / sperm flagellum / nuclear pore / mRNA export from nucleus / ribosomal subunit export from nucleus / U1 snRNA binding / ribosomal small subunit export from nucleus / centriole / GTPase activator activity / protein export from nucleus / mitotic spindle organization / male germ cell nucleus / hippocampus development / Transcriptional regulation by small RNAs / G1/S transition of mitotic cell cycle / recycling endosome / kinetochore / positive regulation of protein import into nucleus / small GTPase binding / protein import into nucleus / GDP binding / melanosome / nuclear envelope / mitotic cell cycle / G protein activity / actin cytoskeleton organization / midbody / ubiquitin-dependent protein catabolic process / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / cadherin binding / protein heterodimerization activity / protein domain specific binding / cell division / GTPase activity / chromatin binding / chromatin / GTP binding / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / magnesium ion binding / protein-containing complex / RNA binding / extracellular exosome / nucleoplasm / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
Ran-specific GTPase-activating protein 1, Ran-binding domain / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / Chromosome region maintenance or exportin repeat / CRM1 / Exportin repeat 2 / CRM1 / Exportin repeat 3 / CRM1 C terminal / Exportin-1, C-terminal / CRM1 C terminal ...Ran-specific GTPase-activating protein 1, Ran-binding domain / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / Chromosome region maintenance or exportin repeat / CRM1 / Exportin repeat 2 / CRM1 / Exportin repeat 3 / CRM1 C terminal / Exportin-1, C-terminal / 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 / Ran GTPase / Small GTPase Ran-type domain profile. / Importin-beta N-terminal domain / Importin-beta N-terminal domain / Importin-beta N-terminal domain profile. / Importin-beta, N-terminal domain / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / 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 / Roll / P-loop containing nucleotide triphosphate hydrolases / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / Leptomycin B / 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 / Resolution: 1.9 Å
AuthorsSun, Q. / Chook, Y.M.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2013
Title: Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
Authors: Sun, Q. / Carrasco, Y.P. / Hu, Y. / Guo, X. / Mirzaei, H. / Macmillan, J. / Chook, Y.M.
History
DepositionSep 27, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 9, 2013Provider: repository / Type: Initial release
Revision 1.1Jan 23, 2013Group: Database references
Revision 1.2Feb 6, 2013Group: Database references
Revision 1.3Jul 26, 2017Group: Source and taxonomy / Category: entity_src_gen
Revision 1.4Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn_type.id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)159,42711
Polymers158,1633
Non-polymers1,2648
Water21,1681175
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9830 Å2
ΔGint-79 kcal/mol
Surface area56470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)105.820, 105.820, 305.231
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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 (E. coli) / 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: 16378.788 Da / Num. of mol.: 1 / Fragment: RanDB1 (UNP residues 62-201)
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 (E. coli) / References: UniProt: P41920
#3: Protein Exportin-1 / CRM1 / Chromosome region maintenance protein 1 / Karyopherin-124


Mass: 117327.625 Da / Num. of mol.: 1 / Fragment: SEE REMARK 999 / Mutation: T539C,R543S,K548E,K579Q,Y1022C
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 (E. coli) / References: UniProt: P30822

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Non-polymers , 5 types, 1183 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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-LBF / Leptomycin B


Mass: 540.731 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H48O6 / Comment: antibiotic*YM
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1175 / Source method: isolated from a natural source / Formula: H2O

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Details

Has protein modificationY
Sequence detailsCHAIN C COMPRISES RESIDUES 1-376 AND 414-1058 OF EXPORTIN-1 (UNP P30822) WITH RESIDUES 377-413 DELETED.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.7 Å3/Da / Density % sol: 54.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
Details: 18% PEG3350, 200 mM ammonium nitrate, 100 mM Bis-Tris, pH 6.6, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID
DetectorType: ADSC QUANTUM 315 / Detector: CCD
RadiationMonochromator: Rosenbaum-Rock high-resolution double-crystal Si(111)
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.9→50 Å / Num. all: 136841 / Num. obs: 136567

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Processing

SoftwareName: REFMAC / Version: 5.6.0117 / Classification: refinement
RefinementResolution: 1.9→50 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.959 / SU B: 8.376 / SU ML: 0.1 / Cross valid method: THROUGHOUT / ESU R: 0.252 / ESU R Free: 0.124 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20884 6882 5 %RANDOM
Rwork0.16542 ---
obs0.16758 129854 99.75 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 23.637 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20 Å20 Å2
2--0.31 Å20 Å2
3----0.61 Å2
Refinement stepCycle: LAST / Resolution: 1.9→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10798 0 77 1175 12050
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0211295
X-RAY DIFFRACTIONr_bond_other_d0.0020.027618
X-RAY DIFFRACTIONr_angle_refined_deg0.9771.96515334
X-RAY DIFFRACTIONr_angle_other_deg2.125318719
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.89751387
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.32825.167538
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.091152080
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.6751550
X-RAY DIFFRACTIONr_chiral_restr0.0560.21751
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212412
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022227
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr2.772311295
X-RAY DIFFRACTIONr_sphericity_free37.2255348
X-RAY DIFFRACTIONr_sphericity_bonded16.859511883
LS refinement shellResolution: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 494 -
Rwork0.368 8708 -
obs--98.38 %
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)
10.13810.0621-0.30261.0224-0.17691.41120.03240.10190.0011-0.00130.0885-0.128-0.13610.014-0.12080.0251-0.02690.00380.23340.00270.11154.12348.90732.059
20.81940.48530.17532.31680.97342.2275-0.0932-0.1068-0.0942-0.3010.0047-0.0603-0.4090.2030.08850.2242-0.05870.06620.09390.02880.06416.64870.24217.098
30.2049-0.13420.00760.33590.05790.50040.04140.0002-0.0101-0.0136-0.0055-0.0343-0.0560.0223-0.03590.0246-0.0299-0.00270.09180.00670.0609-12.78238.51631.028
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A9 - 216
2X-RAY DIFFRACTION1A301 - 302
3X-RAY DIFFRACTION2B80 - 200
4X-RAY DIFFRACTION3C0 - 1052
5X-RAY DIFFRACTION3C1101

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