4HAY

Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(K548E,K579Q)-Ran-RanBP1

PDB DOI: https://doi.org/10.2210/pdb4HAY/pdb

Classification: PROTEIN TRANSPORT/ANTIBIOTIC
Organism(s): Homo sapiens, Saccharomyces cerevisiae
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2012-09-27 Released: 2013-01-09
Deposition Author(s): Sun, Q., Chook, Y.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.230
R-Value Work: 0.187
R-Value Observed: 0.189

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.

Sun, Q., Carrasco, Y.P., Hu, Y., Guo, X., Mirzaei, H., Macmillan, J., Chook, Y.M.

(2013) Proc Natl Acad Sci U S A 110: 1303-1308

PubMed: 23297231 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1073/pnas.1217203110
Primary Citation of Related Structures:
4HAT, 4HAU, 4HAV, 4HAW, 4HAX, 4HAY, 4HAZ, 4HB0, 4HB2, 4HB3, 4HB4

PubMed Abstract:
The polyketide natural product Leptomycin B inhibits nuclear export mediated by the karyopherin protein chromosomal region maintenance 1 (CRM1). Here, we present 1.8- to 2.0-?-resolution crystal structures of CRM1 bound to Leptomycin B and related inhibitors Anguinomycin A and Ratjadone A. Structural and complementary chemical analyses reveal an unexpected mechanism of inhibition involving covalent conjugation and CRM1-mediated hydrolysis of the natural products' lactone rings. Furthermore, mutagenesis reveals the mechanism of hydrolysis by CRM1. The nuclear export signal (NES)-binding groove of CRM1 is able to drive a chemical reaction in addition to binding protein cargoes for transport through the nuclear pore complex.

Organizational Affiliation

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.

Macromolecule Content

Total Structure Weight: 159.76 kDa
Atom Count: 11,886
Modelled Residue Count: 1,335
Deposited Residue Count: 1,379
Unique protein chains: 3

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
GTP-binding nuclear protein Ran	A	216	Homo sapiens	Mutation(s): 0 Gene Names: RAN, ARA24, OK/SW-cl.81 EC: 3.6.5
UniProt & NIH Common Fund Data Resources
Find proteins for P62826 (Homo sapiens) Explore P62826 Go to UniProtKB: P62826
PHAROS: P62826 GTEx: ENSG00000132341
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P62826
Sequence Annotations Expand
Reference Sequence

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(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Ran-specific GTPase-activating protein 1	B	140	Saccharomyces cerevisiae	Mutation(s): 0 Gene Names: YRB1, CST20, HTN1, SFO1, YDR002W, YD8119.08
UniProt
Find proteins for P41920 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c)) Explore P41920 Go to UniProtKB: P41920
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P41920
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 3
Molecule	Chains	Sequence Length	Organism	Details	Image
Exportin-1	C	1,023	Saccharomyces cerevisiae	Mutation(s): 4 Gene Names: CRM1, KAP124, XPO1, YGR218W, G8514
UniProt
Find proteins for P30822 (Saccharomyces cerevisiae (strain ATCC 204508 / S288c)) Explore P30822 Go to UniProtKB: P30822
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P30822
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
LMB Query on LMB Download Ideal Coordinates CCD File SDF format, chain G [auth C] MOL2 format, chain G [auth C] mmCIF format, chain G [auth C]	G [auth C]	Leptomycin B, bound form C₃₃ H₅₂ O₇ GCBBLAVMGONVHO-XYERBDPFSA-N		Interactions Focus chain G [auth C] Interactions & Density Focus chain G [auth C]
GNP Query on GNP Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER C₁₀ H₁₇ N₆ O₁₃ P₃ UQABYHGXWYXDTK-UUOKFMHZSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth C] SDF format, chain I [auth C] SDF format, chain J [auth C] SDF format, chain K [auth C] MOL2 format, chain F [auth A] MOL2 format, chain H [auth C] MOL2 format, chain I [auth C] MOL2 format, chain J [auth C] MOL2 format, chain K [auth C] mmCIF format, chain F [auth A] mmCIF format, chain H [auth C] mmCIF format, chain I [auth C] mmCIF format, chain J [auth C] mmCIF format, chain K [auth C]	F [auth A], H [auth C], I [auth C], J [auth C], K [auth C]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain H [auth C] Focus chain I [auth C] Focus chain J [auth C] Focus chain K [auth C] Interactions & Density Focus chain F [auth A] Focus chain H [auth C] Focus chain I [auth C] Focus chain J [auth C] Focus chain K [auth C]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain L [auth C] SDF format, chain M [auth C] SDF format, chain N [auth C] MOL2 format, chain L [auth C] MOL2 format, chain M [auth C] MOL2 format, chain N [auth C] mmCIF format, chain L [auth C] mmCIF format, chain M [auth C] mmCIF format, chain N [auth C]	L [auth C], M [auth C], N [auth C]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain L [auth C] Focus chain M [auth C] Focus chain N [auth C] Interactions & Density Focus chain L [auth C] Focus chain M [auth C] Focus chain N [auth C]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.30 ?
R-Value Free: 0.230
R-Value Work: 0.187
R-Value Observed: 0.189
Space Group: P 4₃ 2₁ 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 106.165	α = 90
b = 106.165	β = 90
c = 305.659	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-01-09

Deposition Author(s):

Sun, Q.

Chook, Y.M.

Revision History (Full details and data files)

Version 1.0: 2013-01-09
Type: Initial release
Version 1.1: 2013-01-23
Changes: Database references
Version 1.2: 2013-02-06
Changes: Database references
Version 1.3: 2017-07-26
Changes: Source and taxonomy
Version 1.4: 2024-11-06
Changes: Data collection, Database references, Derived calculations, Structure summary