PDBsum entry 6qgd

Apoptosis

PDB id: 6qgd

Contents

Protein chain

512 a.a.

Ligands

GLC-GLC

J1N

Metals

_NA

Waters ×335

PDB id:

6qgd

Name:

Apoptosis

Title:

Structure of human mcl-1 in complex with thienopyrimidine inhibitor

Structure:

Maltose-binding periplasmic protein,induced myeloid leukemia cell differentiation protein mcl-1. Chain: a. Synonym: mbp,mmbp,maltodextrin-binding protein,bcl-2-like protein 3, bcl2-l-3,bcl-2-related protein eat/mcl1,mcl1/eat. Engineered: yes

Source:

Escherichia coli o157:h7, homo sapiens. Human. Organism_taxid: 83334, 9606. Gene: male, z5632, ecs5017, mcl1, bcl2l3. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693. Expression_system_variant: plyss

Resolution:

1.80Å R-factor: 0.179 R-free: 0.208

Authors:

P.Dokurno,J.Murray,J.Davidson,I.Chen,B.Davis,C.J.Graham,R.Harris, A.M.Jordan,N.Matassova,C.Pedder,S.Ray,S.Roughley,J.Smith,C.Walmsley, Y.Wang,N.Whitehead,D.S.Williamson,P.Casara,T.Le Diguarher,J.Hickman, J.Stark,A.Kotschy,O.Geneste,R.E.Hubbard

Key ref:

J.B.Murray et al. (2019). Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1. ACS Omega, 4, 8892-8906. PubMed id: 31459977 DOI: 10.1021/acsomega.9b00611

Date:

11-Jan-19 Release date: 12-Jun-19

Protein chain

P0AEX9  (MALE_ECOLI) -  Maltose/maltodextrin-binding periplasmic protein from Escherichia coli (strain K12)

Seq: 396 a.a.

Struc: 512 a.a.*

Protein chain

Q07820  (MCL1_HUMAN) -  Induced myeloid leukemia cell differentiation protein Mcl-1 from Homo sapiens

Seq: 350 a.a.

Struc: 512 a.a.*

* PDB and UniProt seqs differ at 165 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acsomega.9b00611

ACS Omega 4:8892-8906 (2019)

PubMed id: 31459977

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1.

J.B.Murray, J.Davidson, I.Chen, B.Davis, P.Dokurno, C.J.Graham, R.Harris, A.Jordan, N.Matassova, C.Pedder, S.Ray, S.D.Roughley, J.Smith, C.Walmsley, Y.Wang, N.Whitehead, D.S.Williamson, P.Casara, T.Le Diguarher, J.Hickman, J.Stark, A.Kotschy, O.Geneste, R.E.Hubbard.

ABSTRACT

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using ¹H and ¹⁵N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K_d of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.