PDBsum entry 6g8f

Oxidoreductase

PDB id

6g8f

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Contents

			Protein chain

					475 a.a.

			Ligands

					K0I


					DMS ×4

			Metals

					_CL


					_MN


					_ZN

			Waters ×241

PDB id:

6g8f

Links

Name:

Oxidoreductase

Title:

Crystal structure of utx complexed with gsk-j1

Structure:

Lysine-specific demethylase 6a. Chain: a. Synonym: histone demethylase utx,ubiquitously-transcribed tpr protein on the x chromosome,ubiquitously-transcribed x chromosome tetratricopeptide repeat protein. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: kdm6a, utx. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.04Å

R-factor:

0.195

R-free:

0.236

Authors:

C.Esposito,P.Sledz,A.Caflisch

Key ref:

C.Esposito et al. (2018). In Silico Identification of JMJD3 Demethylase Inhibitors. J Chem Inf Model, 58, 2151-2163. PubMed id: 30226987 DOI: 10.1021/acs.jcim.8b00539

Date:

08-Apr-18

Release date:

10-Oct-18

PROCHECK

	Headers

	References

Protein chain

O15550 (KDM6A_HUMAN) - Lysine-specific demethylase 6A from Homo sapiens

Seq: Struc:

Seq: Struc:

Seq: Struc:					1401 a.a. 475 a.a.

Key:

Secondary structure



		Enzyme reactions

Enzyme class:

E.C.1.14.11.68 - [histone H3]-trimethyl-L-lysine(27) demethylase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

N₆,N₆,N₆-trimethyl-L-lysyl₂₇-[histone H3] + 2 2-oxoglutarate + 2 O2 = N₆-methyl-L-lysyl₂₇-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2

N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3]	+	2 × 2-oxoglutarate	+	2 × O2	=	N(6)-methyl-L-lysyl(27)-[histone H3]	+	2 × formaldehyde	+	2 × succinate	+	2 × CO2

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acs.jcim.8b00539	J Chem Inf Model 58:2151-2163 (2018)
PubMed id: 30226987

In Silico Identification of JMJD3 Demethylase Inhibitors.
C.Esposito, L.Wiedmer, A.Caflisch.

ABSTRACT

In the search for new demethylase inhibitors, we have developed a multistep protocol for in silico screening. Millions of poses generated by high-throughput docking or a 3D-pharmacophore search are first minimized by a classical force field and then filtered by semiempirical quantum mechanical calculations of the interaction energy with a selected set of functional groups in the binding site. The final ranking includes solvation effects which are evaluated in the continuum dielectric approximation (finite-difference Poisson equation). Application of the multistep protocol to JMJD3 jumonji demethylase has resulted in a dozen low-micromolar inhibitors belonging to five different chemical classes. We have solved the crystal structure of JMJD3 inhibitor 8 in the complex with UTX (a demethylase in the same subfamily as JMJD3) which validates the predicted binding mode. Compound 8 is a promising candidate for future optimization as it has a favorable ligand efficiency of 0.32 kcal/mol per nonhydrogen atom.