6G36

Crystal structure of haspin in complex with 5-chlorotubercidin

PDB DOI: https://doi.org/10.2210/pdb6G36/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2018-03-24 Released: 2018-04-18
Deposition Author(s): Heroven, C., Chaikuad, A., Bountra, C., Arrowsmith, C.H., Edwards, A.M., Knapp, S., Structural Genomics Consortium (SGC)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.46 ?
R-Value Free: 0.176
R-Value Work: 0.149
R-Value Observed: 0.151

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Halogen-Aromatic pi Interactions Modulate Inhibitor Residence Times.

Heroven, C., Georgi, V., Ganotra, G.K., Brennan, P., Wolfreys, F., Wade, R.C., Fernandez-Montalvan, A.E., Chaikuad, A., Knapp, S.

(2018) Angew Chem Int Ed Engl 57: 7220-7224

PubMed: 29601130 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1002/anie.201801666
Primary Citation of Related Structures:
6G33, 6G34, 6G35, 6G36, 6G37, 6G38, 6G39, 6G3A

PubMed Abstract:
Prolonged drug residence times may result in longer-lasting drug efficacy, improved pharmacodynamic properties, and "kinetic selectivity" over off-targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active-state (type?I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen-aromatic π?interactions in the haspin-inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding-energy calculations.

Organizational Affiliation

Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, OX3 7DQ, UK.

Macromolecule Content

Total Structure Weight: 41.61 kDa
Atom Count: 3,048
Modelled Residue Count: 338
Deposited Residue Count: 357
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Serine/threonine-protein kinase haspin	A	357	Homo sapiens	Mutation(s): 0 Gene Names: HASPIN, GSG2 EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q8TF76 (Homo sapiens) Explore Q8TF76 Go to UniProtKB: Q8TF76
PHAROS: Q8TF76 GTEx: ENSG00000177602
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8TF76
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
EKH Query on EKH Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	5-chlorotubercidin C₁₁ H₁₃ Cl N₄ O₄ WUHZZVWKGCJQHU-IOSLPCCCSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]
EPE Query on EPE Download Ideal Coordinates CCD File SDF format, chain G [auth A] MOL2 format, chain G [auth A] mmCIF format, chain G [auth A]	G [auth A]	4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID C₈ H₁₈ N₂ O₄ S JKMHFZQWWAIEOD-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Interactions & Density Focus chain G [auth A]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain D [auth A]	D [auth A], E [auth A]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain D [auth A] Focus chain E [auth A] Interactions & Density Focus chain D [auth A] Focus chain E [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
CO Query on CO Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	COBALT (II) ION Co XLJKHNWPARRRJB-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
NA Query on NA Download Ideal Coordinates CCD File SDF format, chain H [auth A] MOL2 format, chain H [auth A] mmCIF format, chain H [auth A]	H [auth A]	SODIUM ION Na FKNQFGJONOIPTF-UHFFFAOYSA-N		Interactions Focus chain H [auth A] Interactions & Density Focus chain H [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.46 ?
R-Value Free: 0.176
R-Value Work: 0.149
R-Value Observed: 0.151
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 77.74	α = 90
b = 78.91	β = 90
c = 79.82	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
iMOSFLM	data reduction
Aimless	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-04-18

Deposition Author(s):

Structural Genomics Consortium (SGC)

Revision History (Full details and data files)

Version 1.0: 2018-04-18
Type: Initial release
Version 1.1: 2018-05-16
Changes: Data collection, Database references
Version 1.2: 2018-06-13
Changes: Data collection, Database references
Version 1.3: 2024-01-17
Changes: Data collection, Database references, Refinement description