6HOY

Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A

PDB DOI: https://doi.org/10.2210/pdb6HOY/pdb

Classification: HYDROLASE
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2018-09-18 Released: 2018-11-14
Deposition Author(s): You, W., Steegborn, C.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.70 Å
R-Value Free: 0.185
R-Value Work: 0.154
R-Value Observed: 0.155

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development.

You, W., Steegborn, C.

(2018) J Med Chem 61: 10922-10928

PubMed: 30395713 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.8b01455
Primary Citation of Related Structures:
6HOY

PubMed Abstract:
Protein lysine deacylases comprise three zinc-dependent families and the NAD ⁺-dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors.

Organizational Affiliation

Department of Biochemistry , University of Bayreuth , Universitätsstraße 30 , 95445 Bayreuth , Germany.

Macromolecule Content

Total Structure Weight: 70.36 kDa
Atom Count: 4,902
Modelled Residue Count: 557
Deposited Residue Count: 604
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
NAD-dependent protein deacetylase sirtuin-6	A, B	302	Homo sapiens	Mutation(s): 0 Gene Names: SIRT6, SIR2L6 EC: 3.5.1 (PDB Primary Data), 2.4.2 (UniProt), 2.3.1 (UniProt), 2.3.1.286 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q8N6T7 (Homo sapiens) Explore Q8N6T7 Go to UniProtKB: Q8N6T7
PHAROS: Q8N6T7 GTEx: ENSG00000077463
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q8N6T7
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
AR6 Query on AR6 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain M [auth B] MOL2 format, chain C [auth A] MOL2 format, chain M [auth B] mmCIF format, chain C [auth A] mmCIF format, chain M [auth B]	C [auth A], M [auth B]	[(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE C₁₅ H₂₃ N₅ O₁₄ P₂ SRNWOUGRCWSEMX-ZQSHOCFMSA-N		Interactions Focus chain C [auth A] Focus chain M [auth B] Interactions & Density Focus chain C [auth A] Focus chain M [auth B]
TSN Query on TSN Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain T [auth B] MOL2 format, chain K [auth A] MOL2 format, chain T [auth B] mmCIF format, chain K [auth A] mmCIF format, chain T [auth B]	K [auth A], T [auth B]	TRICHOSTATIN A C₁₇ H₂₂ N₂ O₃ RTKIYFITIVXBLE-QEQCGCAPSA-N		Interactions Focus chain K [auth A] Focus chain T [auth B] Interactions & Density Focus chain K [auth A] Focus chain T [auth B]
PG4 Query on PG4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain O [auth B] MOL2 format, chain E [auth A] MOL2 format, chain O [auth B] mmCIF format, chain E [auth A] mmCIF format, chain O [auth B]	E [auth A], O [auth B]	TETRAETHYLENE GLYCOL C₈ H₁₈ O₅ UWHCKJMYHZGTIT-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain O [auth B] Interactions & Density Focus chain E [auth A] Focus chain O [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain S [auth B] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain S [auth B] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain S [auth B]	G [auth A] H [auth A] I [auth A] J [auth A] Q [auth B] G [auth A], H [auth A], I [auth A], J [auth A], Q [auth B], R [auth B], S [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B] Interactions & Density Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain S [auth B]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain N [auth B] MOL2 format, chain D [auth A] MOL2 format, chain N [auth B] mmCIF format, chain D [auth A] mmCIF format, chain N [auth B]	D [auth A], N [auth B]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain N [auth B] Interactions & Density Focus chain D [auth A] Focus chain N [auth B]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain L [auth B] SDF format, chain P [auth B] MOL2 format, chain F [auth A] MOL2 format, chain L [auth B] MOL2 format, chain P [auth B] mmCIF format, chain F [auth A] mmCIF format, chain L [auth B] mmCIF format, chain P [auth B]	F [auth A], L [auth B], P [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain L [auth B] Focus chain P [auth B] Interactions & Density Focus chain F [auth A] Focus chain L [auth B] Focus chain P [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
TSN	BindingDB: 6HOY	Ki: min: 2000, max: 4.50e+5 (nM) from 4 assay(s)
TSN	BindingDB: 6HOY	Kd: min: 2.90e+4, max: 4.45e+5 (nM) from 4 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.70 Å
R-Value Free: 0.185
R-Value Work: 0.154
R-Value Observed: 0.155
Space Group: P 6₃

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 91.291	α = 90
b = 91.291	β = 90
c = 143.681	γ = 120

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
XDS	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2018-11-14

Deposition Author(s):

You, W.

Steegborn, C.

Revision History (Full details and data files)

Version 1.0: 2018-11-14
Type: Initial release
Version 1.1: 2019-04-24
Changes: Data collection, Database references
Version 1.2: 2024-01-24
Changes: Data collection, Database references, Refinement description, Structure summary

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Help and Resources

6HOY

Human Sirt6 in complex with ADP-ribose and the inhibitor trichostatin A

Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)