8UG3 | pdb_00008ug3

Crystal structure of KHK-C and compound 23

PDB DOI: https://doi.org/10.2210/pdb8UG3/pdb

Classification: SUGAR BINDING PROTEIN
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2023-10-05 Released: 2023-12-06
Deposition Author(s): Durbin, J.D., Guo, S.Y.
Funding Organization(s): Not funded

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.02 Å
R-Value Free:
0.216 (Depositor), 0.220 (DCC)
R-Value Work:
0.179 (Depositor), 0.180 (DCC)
R-Value Observed:
0.181 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.

Durham, T.B., Hao, J., Spinazze, P., Stack, D.R., Toth, J.L., Massey, S., Mbofana, C.T., Johnston, R.D., Lineswala, J.P., Wrobleski, A., Minguez, J.M., Perez, C., Smith, D.L., Lamar, J., Leon, R., Corkins, C., Durbin, J., Tung, F., Guo, S., Linder, R.J., Yumibe, N., Wang, W., MacKrell, J., Antonellis, M., Mascaro, B.

(2023) J Med Chem 66: 15960-15976

PubMed: 37992274 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.3c01410
Primary Citation of Related Structures:
8UG1, 8UG3

PubMed Abstract:
The identification of clinical candidate LY3522348 (compound 23 ) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient ( S )-2-(2-methylazetidin-1-yl)-6-(1 H -pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile ( 3 ). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.

Organizational Affiliation

Discovery Chemistry Research and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States.

Macromolecule Content

Total Structure Weight: 70.23 kDa
Atom Count: 4,969
Modelled Residue Count: 602
Deposited Residue Count: 630
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Ketohexokinase	A, B	315	Homo sapiens	Mutation(s): 0 Gene Names: KHK EC: 2.7.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for P50053 (Homo sapiens) Explore P50053 Go to UniProtKB: P50053
PHAROS: P50053 GTEx: ENSG00000138030
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P50053
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
WRE (Subject of Investigation/LOI) Query on WRE Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain G [auth B] MOL2 format, chain C [auth A] MOL2 format, chain G [auth B] mmCIF format, chain C [auth A] mmCIF format, chain G [auth B]	C [auth A], G [auth B]	2-[(4P)-4-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrazol-1-yl]-1-(piperazin-1-yl)ethan-1-one C₁₈ H₂₂ F₃ N₇ O HAUDFIFEGDNKJX-LBPRGKRZSA-N		Interactions Focus chain C [auth A] Focus chain G [auth B] Interactions & Density Focus chain C [auth A] Focus chain G [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B]	D [auth A] E [auth A] F [auth A] H [auth B] I [auth B] D [auth A], E [auth A], F [auth A], H [auth B], I [auth B], J [auth B], K [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain H [auth B] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain L [auth B] SDF format, chain M [auth B] MOL2 format, chain L [auth B] MOL2 format, chain M [auth B] mmCIF format, chain L [auth B] mmCIF format, chain M [auth B]	L [auth B], M [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain L [auth B] Focus chain M [auth B] Interactions & Density Focus chain L [auth B] Focus chain M [auth B]