8im3

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Crystal structure of human HPPD complexed with compound a10

Structural highlights

8im3 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.78Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HPPD_HUMAN Defects in HPD are the cause of tyrosinemia type 3 (TYRO3) [MIM:276710. TYRO3 is an inborn error of metabolism characterized by elevations of tyrosine in the blood and urine, seizures and mild mental retardation.^[1] ^[2] Defects in HPD are a cause of hawkinsinuria (HAWK) [MIM:140350. HAWK is an inborn error of tyrosine metabolism characterized by failure to thrive, persistent metabolic acidosis, fine and sparse hair, and excretion of the unusual cyclic amino acid metabolite, hawkinsin, in the urine.^[3]

Function

HPPD_HUMAN Key enzyme in the degradation of tyrosine.

Publication Abstract from PubMed

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and alpha7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.

Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.,Dong J, Xiao H, Chen JN, Zheng BF, Xu YL, Chen MX, Yang WC, Lin HY, Yang GF Structure. 2023 Sep 21:S0969-2126(23)00328-3. doi: 10.1016/j.str.2023.09.005. PMID:37794595^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ruetschi U, Cerone R, Perez-Cerda C, Schiaffino MC, Standing S, Ugarte M, Holme E. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Hum Genet. 2000 Jun;106(6):654-62. PMID:10942115
↑ Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F. Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Mol Genet Metab. 2000 Nov;71(3):506-10. PMID:11073718 doi:10.1006/mgme.2000.3085
↑ Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F. Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Mol Genet Metab. 2000 Nov;71(3):506-10. PMID:11073718 doi:10.1006/mgme.2000.3085
↑ Dong J, Xiao H, Chen JN, Zheng BF, Xu YL, Chen MX, Yang WC, Lin HY, Yang GF. Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors. Structure. 2023 Sep 21:S0969-2126(23)00328-3. PMID:37794595 doi:10.1016/j.str.2023.09.005