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 journalArticlepeer-review

36 Citations (Scopus)


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
Issue number48
Publication statusPublished - 2002 Nov 29
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase'. Together they form a unique fingerprint.

Cite this