4MQ1

The crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimidine inhibitor

PDB DOI: https://doi.org/10.2210/pdb4MQ1/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2013-09-15 Released: 2013-12-11
Deposition Author(s): Lukacs, C.M., Janson, C.A., Garvie, C., Liang, L.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.35 Å
R-Value Free: 0.246
R-Value Work: 0.202
R-Value Observed: 0.204

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 1.4 of the entry. See complete history.

Literature

Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

Anderson, K., Chen, Y., Chen, Z., Dominique, R., Glenn, K., He, Y., Janson, C., Luk, K.C., Lukacs, C., Polonskaia, A., Qiao, Q., Railkar, A., Rossman, P., Sun, H., Xiang, Q., Vilenchik, M., Wovkulich, P., Zhang, X.

(2013) Bioorg Med Chem Lett 23: 6610-6615

PubMed: 24239188 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2013.10.055
Primary Citation of Related Structures:
4MQ1, 4MQ2

PubMed Abstract:
DYRK1B is a kinase over-expressed in certain cancer cells (including colon, ovarian, pancreatic, etc.). Recent publications have demonstrated inhibition of DYRK1B could be an attractive target for cancer therapy. From a data-mining effort, the team has discovered analogues of pyrido[2,3-d]pyrimidines as potent enantio-selective inhibitors of DYRK1B. Cells treated with a tool compound from this series showed the same cellular effects as down regulation of DYRK1B with siRNA. Such effects are consistent with the proposed mechanism of action. Progress of the SAR study is presented.

Organizational Affiliation

Discovery Chemistry, Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, NJ 07110, USA.

Macromolecule Content

Total Structure Weight: 172.69 kDa
Atom Count: 11,696
Modelled Residue Count: 1,353
Deposited Residue Count: 1,444
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dual specificity tyrosine-phosphorylation-regulated kinase 1A	A, B, C, D	361	Homo sapiens	Mutation(s): 0 Gene Names: DYRK1A, DYRK, MNB, MNBH EC: 2.7.12.1 (PDB Primary Data), 2.7.11.23 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q13627 (Homo sapiens) Explore Q13627 Go to UniProtKB: Q13627
PHAROS: Q13627 GTEx: ENSG00000157540
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q13627
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
2C3 Query on 2C3 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain J [auth B] SDF format, chain O [auth C] SDF format, chain S [auth D] MOL2 format, chain E [auth A] MOL2 format, chain J [auth B] MOL2 format, chain O [auth C] MOL2 format, chain S [auth D] mmCIF format, chain E [auth A] mmCIF format, chain J [auth B] mmCIF format, chain O [auth C] mmCIF format, chain S [auth D]	E [auth A], J [auth B], O [auth C], S [auth D]	N-(5-{[(1R)-3-amino-1-(3-chlorophenyl)propyl]carbamoyl}-2-chlorophenyl)-2-methoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide C₂₅ H₂₂ Cl₂ N₆ O₄ KUFCYNGJQRKYSQ-LJQANCHMSA-N		Interactions Focus chain E [auth A] Focus chain J [auth B] Focus chain O [auth C] Focus chain S [auth D] Interactions & Density Focus chain E [auth A] Focus chain J [auth B] Focus chain O [auth C] Focus chain S [auth D]
1PE Query on 1PE Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain K [auth B] SDF format, chain L [auth B] SDF format, chain P [auth C] SDF format, chain T [auth D] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain K [auth B] MOL2 format, chain L [auth B] MOL2 format, chain P [auth C] MOL2 format, chain T [auth D] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain K [auth B] mmCIF format, chain L [auth B] mmCIF format, chain P [auth C] mmCIF format, chain T [auth D]	F [auth A] G [auth A] K [auth B] L [auth B] P [auth C] F [auth A], G [auth A], K [auth B], L [auth B], P [auth C], T [auth D]	PENTAETHYLENE GLYCOL C₁₀ H₂₂ O₆ JLFNLZLINWHATN-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain P [auth C] Focus chain T [auth D] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain K [auth B] Focus chain L [auth B] Focus chain P [auth C] Focus chain T [auth D]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain M [auth B] SDF format, chain N [auth B] SDF format, chain Q [auth C] SDF format, chain R [auth C] SDF format, chain U [auth D] SDF format, chain V [auth D] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain M [auth B] MOL2 format, chain N [auth B] MOL2 format, chain Q [auth C] MOL2 format, chain R [auth C] MOL2 format, chain U [auth D] MOL2 format, chain V [auth D] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain M [auth B] mmCIF format, chain N [auth B] mmCIF format, chain Q [auth C] mmCIF format, chain R [auth C] mmCIF format, chain U [auth D] mmCIF format, chain V [auth D]	H [auth A] I [auth A] M [auth B] N [auth B] Q [auth C] H [auth A], I [auth A], M [auth B], N [auth B], Q [auth C], R [auth C], U [auth D], V [auth D]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain H [auth A] Focus chain I [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain Q [auth C] Focus chain R [auth C] Focus chain U [auth D] Focus chain V [auth D] Interactions & Density Focus chain H [auth A] Focus chain I [auth A] Focus chain M [auth B] Focus chain N [auth B] Focus chain Q [auth C] Focus chain R [auth C] Focus chain U [auth D] Focus chain V [auth D]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
PTR Query on PTR	A, B, C, D	L-PEPTIDE LINKING	C₉ H₁₂ N O₆ P		TYR

Binding Affinity Annotations
ID	Source	Binding Affinity
2C3	BindingDB: 4MQ1	IC50: 12 (nM) from 1 assay(s)
2C3	PDBBind: 4MQ1	IC50: 12 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.35 Å
R-Value Free: 0.246
R-Value Work: 0.202
R-Value Observed: 0.204
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 263.843	α = 90
b = 64.939	β = 115.16
c = 140.461	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-12-11

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2013-12-11
Type: Initial release
Version 1.1: 2013-12-18
Changes: Database references
Version 1.2: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description
Version 1.3: 2023-12-06
Changes: Data collection
Version 1.4: 2024-11-27
Changes: Structure summary

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4MQ1

The crystal structure of DYRK1a with a bound pyrido[2,3-d]pyrimidine inhibitor

Pyrido[2,3-d]pyrimidines: Discovery and preliminary SAR of a novel series of DYRK1B and DYRK1A inhibitors.

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)