4D2W

Structure of MELK in complex with inhibitors

PDB DOI: https://doi.org/10.2210/pdb4D2W/pdb

Classification: TRANSFERASE
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): Yes

Deposited: 2014-05-13 Released: 2014-10-08
Deposition Author(s): Johnson, C.N., Berdini, V., Beke, L., Bonnet, P., Brehmer, D., Coyle, J.E., Day, P.J., Frederickson, M., Freyne, E.J.E., Gilissen, R.A.H.J., Hamlett, C.C.F., Howard, S., Meerpoel, L., McMenamin, R., Patel, S., Rees, D.C., Sharff, A., Sommen, F., Wu, T., Linders, J.T.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.92 Å
R-Value Free: 0.247
R-Value Work: 0.201
R-Value Observed: 0.203

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase

Johnson, C.N., Berdini, V., Beke, L., Bonnet, P., Brehmer, D., Coyle, J.E., Day, P.J., Frederickson, M., Freyne, E.J.E., Gilissen, R.A.H.J., Hamlett, C.C.F., Howard, S., Meerpoel, L., Mcmenamin, R., Patel, S., Rees, D.C., Sharff, A., Sommen, F., Wu, T., Linders, J.T.M.

(2015) ACS Med Chem Lett 6: 25

PubMed: 25589925 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/ml5001245
Primary Citation of Related Structures:
4D2P, 4D2T, 4D2V, 4D2W, 4UMP, 4UMQ, 4UMR

PubMed Abstract:
Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 μM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology.

Organizational Affiliation

Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.

Macromolecule Content

Total Structure Weight: 164.89 kDa
Atom Count: 11,529
Modelled Residue Count: 1,276
Deposited Residue Count: 1,424
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE	A, B, C, D	356	Homo sapiens	Mutation(s): 7 EC: 2.7.11.1 (PDB Primary Data), 2.7.10.2 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q14680 (Homo sapiens) Explore Q14680 Go to UniProtKB: Q14680
PHAROS: Q14680 GTEx: ENSG00000165304
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q14680
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 1 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NF5 Query on NF5 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth B] SDF format, chain G [auth C] SDF format, chain H [auth D] MOL2 format, chain E [auth A] MOL2 format, chain F [auth B] MOL2 format, chain G [auth C] MOL2 format, chain H [auth D] mmCIF format, chain E [auth A] mmCIF format, chain F [auth B] mmCIF format, chain G [auth C] mmCIF format, chain H [auth D]	E [auth A], F [auth B], G [auth C], H [auth D]	4-bromo-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)benzamide C₁₇ H₁₇ Br N₂ O YMOUEQZHQYODQT-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth B] Focus chain G [auth C] Focus chain H [auth D] Interactions & Density Focus chain E [auth A] Focus chain F [auth B] Focus chain G [auth C] Focus chain H [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.92 Å
R-Value Free: 0.247
R-Value Work: 0.201
R-Value Observed: 0.203
Space Group: P 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 65.956	α = 85.74
b = 74.947	β = 70.07
c = 78.216	γ = 89.94

Software Package:

Software Name	Purpose
BUSTER	refinement
d*TREK	data reduction
d*TREK	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-10-08

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2014-10-08
Type: Initial release
Version 1.1: 2015-01-28
Changes: Database references
Version 1.2: 2018-04-04
Changes: Data collection
Version 1.3: 2024-05-08
Changes: Data collection, Database references, Derived calculations, Other

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Help and Resources

4D2W

Structure of MELK in complex with inhibitors

Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)