5MES

MCL1 FAB COMPLEX IN COMPLEX WITH COMPOUND 29


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl-1 Inhibitors.

Johannes, J.W.Bates, S.Beigie, C.Belmonte, M.A.Breen, J.Cao, S.Centrella, P.A.Clark, M.A.Cuozzo, J.W.Dumelin, C.E.Ferguson, A.D.Habeshian, S.Hargreaves, D.Joubran, C.Kazmirski, S.Keefe, A.D.Lamb, M.L.Lan, H.Li, Y.Ma, H.Mlynarski, S.Packer, M.J.Rawlins, P.B.Robbins, D.W.Shen, H.Sigel, E.A.Soutter, H.H.Su, N.Troast, D.M.Wang, H.Wickson, K.F.Wu, C.Zhang, Y.Zhao, Q.Zheng, X.Hird, A.W.

(2017) ACS Med Chem Lett 8: 239-244

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00464
  • Primary Citation of Related Structures:  
    5KU9, 5MES, 5MEV

  • PubMed Abstract: 

    Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1 , a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together. This proximity allowed for the linking of the two ends of the peptide to form a macrocycle. Macrocyclization resulted in an approximately 10-fold improvement in binding potency. Further exploration of a key hydrophobic interaction with Mcl-1 protein and also with the moiety that engages Arg256 led to additional potency improvements. The use of protein-ligand crystal structures and binding kinetics contributed to the design and understanding of the potency gains. Optimized compound 26 is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at only 5 μM and Bcl-xL at >99 μM, and induces cleaved caspase-3 in MV4-11 cells with an IC 50 of 3 μM after 6 h.


  • Organizational Affiliation

    AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, 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 homolog,Induced myeloid leukemia cell differentiation protein Mcl-1162Mus musculusHomo sapiens
This entity is chimeric
Mutation(s): 0 
Gene Names: Mcl1MCL1BCL2L3
UniProt & NIH Common Fund Data Resources
Find proteins for P97287 (Mus musculus)
Explore P97287 
Go to UniProtKB:  P97287
IMPC:  MGI:101769
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 GroupsP97287Q07820
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Heavy ChainB [auth H]230Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Light ChainC [auth L]226Homo sapiensMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
7LT
Query on 7LT

Download Ideal Coordinates CCD File 
D [auth A](5~{R},13~{S},17~{S})-5-[[4-chloranyl-3-(2-phenylethyl)phenyl]methyl]-13-[(4-chlorophenyl)methyl]-8-methyl-1,4,8,12,16-pentazatricyclo[15.8.1.0^{20,25}]hexacosa-20(25),21,23-triene-3,7,15,26-tetrone
C44 H49 Cl2 N5 O4
OWZLWLCCVAZXNM-UIJXAYEMSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7LT Binding MOAD:  5MES Kd: 340 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.24 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 168.47α = 90
b = 40.33β = 126.11
c = 102.84γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-01-18
    Type: Initial release
  • Version 1.1: 2017-03-01
    Changes: Database references
  • Version 1.2: 2017-03-08
    Changes: Database references