4ZBF

Mcl-1 complexed with small molecules


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history

Re-refinement Note

A newer entry is available that reflects an alternative modeling of the original data: 4ZBI


Literature

Discovery of tricyclic indoles that potently inhibit mcl-1 using fragment-based methods and structure-based design.

Burke, J.P.Bian, Z.Shaw, S.Zhao, B.Goodwin, C.M.Belmar, J.Browning, C.F.Vigil, D.Friberg, A.Camper, D.V.Rossanese, O.W.Lee, T.Olejniczak, E.T.Fesik, S.W.

(2015) J Med Chem 58: 3794-3805

  • DOI: https://doi.org/10.1021/jm501984f
  • Primary Citation of Related Structures:  
    4ZBF, 4ZBI

  • PubMed Abstract: 

    Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.


  • Organizational Affiliation

    Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Induced myeloid leukemia cell differentiation protein Mcl-1
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L
157Homo sapiensMutation(s): 0 
Gene Names: MCL1BCL2L3
UniProt & NIH Common Fund Data Resources
Find proteins for Q07820 (Homo sapiens)
Explore Q07820 
Go to UniProtKB:  Q07820
PHAROS:  Q07820
GTEx:  ENSG00000143384 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07820
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4M7
Query on 4M7

Download Ideal Coordinates CCD File 
M [auth A]
N [auth B]
O [auth C]
P [auth D]
Q [auth E]
M [auth A],
N [auth B],
O [auth C],
P [auth D],
Q [auth E],
R [auth F],
S [auth G],
T [auth H],
U [auth I],
V [auth J],
W [auth K],
X [auth L]
(1R)-7-[3-(naphthalen-1-yloxy)propyl]-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid 1-oxide
C25 H23 N O4 S
RWBITVLVWMQUOJ-WJOKGBTCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4M7 Binding MOAD:  4ZBF Ki: 74 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.183 
  • R-Value Observed: 0.184 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.722α = 90
b = 134.405β = 100.27
c = 135.332γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data

  • Released Date: 2015-04-29 
  • Deposition Author(s): Zhao, B.

Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesBOA29XS129TO22

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-29
    Type: Initial release
  • Version 1.1: 2015-05-27
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations, Source and taxonomy, Structure summary
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references