4WGI

A Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)

PDB DOI: https://doi.org/10.2210/pdb4WGI/pdb

Classification: apoptosis/inhibitor
Organism(s): Escherichia coli O157:H7, Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2014-09-18 Released: 2014-11-19
Deposition Author(s): Clifton, M.C., Fairman, J.W., Fang, C., D'Souza, B., Fulroth, B., Leed, A., McCarren, P., Wang, L., Wang, Y., Kaushik, V., Palmer, M., Wei, G., Golub, T.R., Hubbard, B.K., Serrano-Wu, M.H.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.213
R-Value Work: 0.177
R-Value Observed: 0.179

Starting Model: experimental
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Ligand Structure Quality Assessment

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Literature

Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1).

Fang, C., D'Souza, B., Thompson, C.F., Clifton, M.C., Fairman, J.W., Fulroth, B., Leed, A., McCarren, P., Wang, L., Wang, Y., Feau, C., Kaushik, V.K., Palmer, M., Wei, G., Golub, T.R., Hubbard, B.K., Serrano-Wu, M.H.

(2014) ACS Med Chem Lett 5: 1308-1312

PubMed: 25516789 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/ml500388q
Primary Citation of Related Structures:
4WGI

PubMed Abstract:
A direct binding screen of 100 000 sp(3)-rich molecules identified a single diastereomer of a macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). A comprehensive toolbox of biophysical methods was applied to validate the original hit and subsequent analogues and also established a binding mode competitive with NOXA BH3 peptide. X-ray crystallography of ligand bound to MCL1 reveals a remarkable ligand/protein shape complementarity that diverges from previously disclosed MCL1 inhibitor costructures.

Organizational Affiliation

Broad Institute , 415 Main Street, Cambridge, Massachusetts 02142, United States.

Macromolecule Content

Total Structure Weight: 58.8 kDa
Atom Count: 4,507
Modelled Residue Count: 513
Deposited Residue Count: 518
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1	A	518	Escherichia coli O157:H7, Homo sapiens This entity is chimeric	Mutation(s): 3 Gene Names: malE, Z5632, ECs5017, MCL1, BCL2L3
UniProt & NIH Common Fund Data Resources
Find proteins for Q07820 (Homo sapiens) Explore Q07820 Go to UniProtKB: Q07820
PHAROS: Q07820 GTEx: ENSG00000143384
Find proteins for P0AEY0 (Escherichia coli O157:H7) Explore P0AEY0 Go to UniProtKB: P0AEY0
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Groups	P0AEY0Q07820
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

Help

Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose	B	2		N/A	Interactions Focus chain B Interactions & Density Focus chain B
Glycosylation Resources
GlyTouCan: G07411ON GlyCosmos: G07411ON

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
3M6 Query on 3M6 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	(2S)-2-[(2S,3R)-10-{[(4-fluorophenyl)sulfonyl]amino}-3-methyl-2-[(methyl{[4-(trifluoromethyl)phenyl]carbamoyl}amino)methyl]-6-oxo-3,4-dihydro-2H-1,5-benzoxazocin-5(6H)-yl]propanoic acid C₃₀ H₃₀ F₄ N₄ O₇ S XAEPMFMCFFIZDH-FUMQJTLXSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
FMT Query on FMT 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 I [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] 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 I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] 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 I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A]	E [auth A] F [auth A] G [auth A] H [auth A] I [auth A] E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], N [auth A]	FORMIC ACID C H₂ O₂ BDAGIHXWWSANSR-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
3M6	BindingDB: 4WGI	Kd: min: 1900, max: 6000 (nM) from 2 assay(s)
3M6	BindingDB: 4WGI	IC50: 4500 (nM) from 1 assay(s)

Biologically Interesting Molecules (External Reference) 1 Unique

Entity ID: 2
ID	Chains	Name	Type/Class	2D Diagram	3D Interactions
PRD_900001 Query on PRD_900001	B	alpha-maltose	Oligosaccharide / Nutrient		Interactions Focus chain B Interactions & Density Focus chain B

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.85 Å
R-Value Free: 0.213
R-Value Work: 0.177
R-Value Observed: 0.179
Space Group: P 2₁ 2₁ 2

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 99.3	α = 90
b = 135.87	β = 90
c = 37.69	γ = 90

Software Package:

Software Name	Purpose
XDS	data reduction
PHENIX	refinement
PDB_EXTRACT	data extraction
XSCALE	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-11-19

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-11-19
Type: Initial release
Version 1.1: 2014-12-31
Changes: Database references
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Non-polymer description, Source and taxonomy, Structure summary
Version 2.1: 2023-09-27
Changes: Data collection, Database references, Refinement description, Structure summary

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Help and Resources

4WGI

A Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1)

Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1).

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Entity ID: 2