8hub

From Proteopedia

AMP deaminase 2 in complex with an inhibitor

Structural highlights

8hub is a 4 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 3.25Å
Ligands:	N4X, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AMPD2_HUMAN Autosomal recessive spastic paraplegia type 63;Pontocerebellar hypoplasia type 9. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

AMPD2_HUMAN AMP deaminase plays a critical role in energy metabolism. Catalyzes the deamination of AMP to IMP and plays an important role in the purine nucleotide cycle.^[1]

Publication Abstract from PubMed

AMP deaminase 2 (AMPD2) has been thought to play an important role in energy homeostasis and immuno-oncology, while selective AMPD2 inhibitors are highly demanded to clarify the physiological function of AMPD2. In this report, we describe selective AMPD2 inhibitors inducing allosteric modulation. Based on hypothesis that compounds that exhibit increased inhibition by preincubation would cause conformational change of the enzyme, starting from HTS hit compound 4, we discovered compound 8 through the SAR study. From X-ray structural information of 8, this chemical series has a novel mechanism of action that changes the substrate pocket to prevent AMP from binding. Further elaboration of compound 8 led to the tool compound 21 which exhibited potent inhibitory activity of AMPD2 in ex vivo evaluation of mouse liver.

The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action.,Kitao Y, Saito T, Watanabe S, Ohe Y, Takahashi K, Akaki T, Adachi T, Doi S, Yamanaka K, Murai Y, Oba M, Suzuki T Bioorg Med Chem Lett. 2023 Jan 15;80:129110. doi: 10.1016/j.bmcl.2022.129110. , Epub 2022 Dec 20. PMID:36563792^[2]

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

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Citations

reviews cite this structure

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References

↑ Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, Gleeson JG. AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder. Cell. 2013 Aug 1;154(3):505-17. doi: 10.1016/j.cell.2013.07.005. PMID:23911318 doi:http://dx.doi.org/10.1016/j.cell.2013.07.005
↑ Kitao Y, Saito T, Watanabe S, Ohe Y, Takahashi K, Akaki T, Adachi T, Doi S, Yamanaka K, Murai Y, Oba M, Suzuki T. The discovery of 3,3-dimethyl-1,2,3,4-tetrahydroquinoxaline-1-carboxamides as AMPD2 inhibitors with a novel mechanism of action. Bioorg Med Chem Lett. 2023 Jan 15;80:129110. PMID:36563792 doi:10.1016/j.bmcl.2022.129110