Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase

Hye Yeon Kim, Yong Seok Heo, Jin Hwan Kim, Min Hye Park, Jinho Moon, Eunmi Kim, Doyoon Kwon, Jeongmin Yoon, Dongkyu Shin, Eui june Jeong, Sam Yong Park, Tae Gyu Lee, Young Ho Jeon, Seonggu Ro, Joong Myung Cho, Kwang Yeon Hwang

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Human phosphoserine phosphatase (HPSP) regulates the levels of glycine and D-serine, the putative co-agonists for the glycine site of the NMDA receptor in the brain. Here, we describe the first crystal structures of the HPSP in complexes with the competitive inhibitor 2-amino-3-phosphonopropionic acid (AP3) at 2.5 Å, and the phosphate ion (Pi) and the product uncompetitive inhibitor L-serine (HPSP·L-Ser·Pi) at 2.8 Å. The complex structures reveal that the open-closed environmental change of the active site, generated by local rearrangement of the α-helical bundle domain, is important to substrate recognition and hydrolysis. The maximal extent of this structural rearrangement is shown to be about 13 Å at the L4 loop and about 25° at the helix α3. Both the structural change and mutagenesis data suggest that Arg-65 and Glu-29 play an important role in the binding of the substrate. Interestingly, the AP3 binding mode turns out to be significantly different from that of the natural substrate, phospho-L-serine, and the HPSP·L- Ser·Pi structure provides a structural basis for the feedback control mechanism of serine. These analyses allow us to provide a clear model for the mechanism of HPSP and a framework for structure-based drug development.

Original languageEnglish
Pages (from-to)46651-46658
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number48
DOIs
Publication statusPublished - 2002 Nov 29
Externally publishedYes

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Serine
Glycine
Substrates
Mutagenesis
N-Methyl-D-Aspartate Receptors
Feedback control
Hydrolysis
Brain
Catalytic Domain
Crystal structure
Phosphates
Ions
phosphoserine phosphatase
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry

Cite this

Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase. / Kim, Hye Yeon; Heo, Yong Seok; Kim, Jin Hwan; Park, Min Hye; Moon, Jinho; Kim, Eunmi; Kwon, Doyoon; Yoon, Jeongmin; Shin, Dongkyu; Jeong, Eui june; Yong Park, Sam; Lee, Tae Gyu; Jeon, Young Ho; Ro, Seonggu; Cho, Joong Myung; Hwang, Kwang Yeon.

In: Journal of Biological Chemistry, Vol. 277, No. 48, 29.11.2002, p. 46651-46658.

Research output: Contribution to journalArticle

Kim, HY, Heo, YS, Kim, JH, Park, MH, Moon, J, Kim, E, Kwon, D, Yoon, J, Shin, D, Jeong, EJ, Yong Park, S, Lee, TG, Jeon, YH, Ro, S, Cho, JM & Hwang, KY 2002, 'Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase', Journal of Biological Chemistry, vol. 277, no. 48, pp. 46651-46658. https://doi.org/10.1074/jbc.M204866200
Kim, Hye Yeon ; Heo, Yong Seok ; Kim, Jin Hwan ; Park, Min Hye ; Moon, Jinho ; Kim, Eunmi ; Kwon, Doyoon ; Yoon, Jeongmin ; Shin, Dongkyu ; Jeong, Eui june ; Yong Park, Sam ; Lee, Tae Gyu ; Jeon, Young Ho ; Ro, Seonggu ; Cho, Joong Myung ; Hwang, Kwang Yeon. / Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 48. pp. 46651-46658.
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AU - Lee, Tae Gyu

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