Tags

Type your tag names separated by a space and hit enter

Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein.
Biomolecules 2020; 10(1)B

Abstract

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.

Authors+Show Affiliations

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.Laboratory of Molecular and Stem Cell Pharmacology, College of Pharmacy, Chung-Ang University, Seoul 06974, Korea.Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31935861

Citation

Kim, Kyung Rok, et al. "Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein." Biomolecules, vol. 10, no. 1, 2020.
Kim KR, Kim KA, Park JS, et al. Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein. Biomolecules. 2020;10(1).
Kim, K. R., Kim, K. A., Park, J. S., Jang, J. Y., Choi, Y., Lee, H. H., ... Han, B. W. (2020). Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein. Biomolecules, 10(1), doi:10.3390/biom10010090.
Kim KR, et al. Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein. Biomolecules. 2020 Jan 6;10(1) PubMed PMID: 31935861.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein. AU - Kim,Kyung Rok, AU - Kim,Kyung A, AU - Park,Joon Sung, AU - Jang,Jun Young, AU - Choi,Yuri, AU - Lee,Hyung Ho, AU - Lee,Dong Chul, AU - Park,Kyung Chan, AU - Yeom,Young Il, AU - Kim,Hyun-Jung, AU - Han,Byung Woo, Y1 - 2020/01/06/ PY - 2019/10/18/received PY - 2019/12/31/revised PY - 2020/01/01/accepted PY - 2020/1/16/entrez KW - NDRG3 KW - crystal structure KW - unfolded helix KW - α/β-hydrolase fold JF - Biomolecules JO - Biomolecules VL - 10 IS - 1 N2 - The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3. SN - 2218-273X UR - https://www.unboundmedicine.com/medline/citation/31935861/Structural_and_Biophysical_Analyses_of_Human_N-Myc_Downstream-Regulated_Gene_3_(NDRG3)_Protein L2 - http://www.mdpi.com/resolver?pii=biom10010090 DB - PRIME DP - Unbound Medicine ER -