5MF6

Human Sirt6 in complex with activator UBCS039

PDB DOI: https://doi.org/10.2210/pdb5MF6/pdb

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

Deposited: 2016-11-17 Released: 2016-12-28
Deposition Author(s): Steegborn, C., You, W., Kambach, C.
Funding Organization(s): Oberfrankenstiftung

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.87 ?
R-Value Free: 0.220
R-Value Work: 0.190
R-Value Observed: 0.191

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 Activation by Synthetic Small Molecules.

You, W., Rotili, D., Li, T.M., Kambach, C., Meleshin, M., Schutkowski, M., Chua, K.F., Mai, A., Steegborn, C.

(2017) Angew Chem Int Ed Engl 56: 1007-1011

PubMed: 27990725 Search on PubMed
DOI: https://doi.org/10.1002/anie.201610082
Primary Citation of Related Structures:
5MF6, 5MFP, 5MFZ, 5MGN

PubMed Abstract:
Sirtuins are protein deacylases regulating metabolism and stress responses, and are implicated in aging-related diseases. Small molecule activators for the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, such as for cancer. Activators are available for Sirt1 and exploit its unique N-terminus, whereas drug-like activators for Sirt2-7 are lacking. We synthesized and screened pyrrolo[1,2-a]quinoxaline derivatives, yielding the first synthetic Sirt6 activators. Biochemical assays show direct, substrate-independent compound binding to the Sirt6 catalytic core and potent activation of Sirt6-dependent deacetylation of peptide substrates and complete nucleosomes. Crystal structures of Sirt6/activator complexes reveal that the compounds bind to a Sirt6-specific acyl channel pocket and identify key interactions. Our results establish potent Sirt6 activation with small molecules and provide a structural basis for further development of Sirt6 activators as tools and therapeutics.

Organizational Affiliation

Universit?t Bayreuth, Lehrstuhl Biochemie und Forschungszentrum für Biomakromoleküle, Universit?tsstr. 30, 95447, Bayreuth, Germany.

Macromolecule Content

Total Structure Weight: 70.11 kDa
Atom Count: 4,701
Modelled Residue Count: 557
Deposited Residue Count: 604
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(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]
7M2 Query on 7M2 Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain T [auth B] MOL2 format, chain L [auth A] MOL2 format, chain T [auth B] mmCIF format, chain L [auth A] mmCIF format, chain T [auth B]	L [auth A], T [auth B]	(4~{R})-4-pyridin-3-yl-4,5-dihydropyrrolo[1,2-a]quinoxaline C₁₆ H₁₃ N₃ BSOBGTYXYGHUTD-MRXNPFEDSA-N		Interactions Focus chain L [auth A] Focus chain T [auth B] Interactions & Density Focus chain L [auth A] Focus chain T [auth B]
PGE Query on PGE Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	TRIETHYLENE GLYCOL C₆ H₁₄ O₄ ZIBGPFATKBEMQZ-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] SDF format, chain R [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B]	E [auth A] F [auth A] G [auth A] H [auth A] O [auth B] E [auth A], F [auth A], G [auth A], H [auth A], O [auth B], P [auth B], Q [auth B], R [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [auth B] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Focus chain R [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 I [auth A] SDF format, chain J [auth A] SDF format, chain S [auth B] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain S [auth B] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain S [auth B]	I [auth A], J [auth A], S [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain J [auth A] Focus chain S [auth B] Interactions & Density Focus chain I [auth A] Focus chain J [auth A] Focus chain S [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.87 ?
R-Value Free: 0.220
R-Value Work: 0.190
R-Value Observed: 0.191
Space Group: P 6₃

Unit Cell:

Length ( ? )	Angle ( ? )
a = 91.3	α = 90
b = 91.3	β = 90
c = 144.317	γ = 120

Software Package:

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

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2016-12-28

Deposition Author(s):

Steegborn, C.

You, W.

Kambach, C.

Funding Organization	Location	Grant Number
Oberfrankenstiftung	Germany	--

Revision History (Full details and data files)

Version 1.0: 2016-12-28
Type: Initial release
Version 1.1: 2017-01-25
Changes: Database references
Version 1.2: 2024-01-17
Changes: Data collection, Database references, Refinement description, Structure summary

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Help and Resources

5MF6

Human Sirt6 in complex with activator UBCS039

Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

Expand

Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)