title: Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase.
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 A, and the phosphate ion (Pi) and the product uncompetitive inhibitor l-serine (HPSP.l-Ser.Pi) at 2.8 A. The complex structures reveal that the open-closed environmental change of the active site, generated by local rearrangement of the alpha-helical bundle domain, is important to substrate recognition and hydrolysis. The maximal extent of this structural rearrangement is shown to be about 13 A at the L4 loop and about 25 degrees at the helix alpha3. 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.
authors.affiliation: Divison of Drug Discovery, CrystalGenomics Incorporated, Daeduck Biocommunity, Jeonmin-dong, Yuseong-gu, Taejeon City, South Korea 305-600.
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Kim
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Kim
authors.forename: Min Hye
authors.initials: MH
authors.lastname: Park
authors.forename: Jinho
authors.initials: J
authors.lastname: Moon
authors.forename: Eunmi
authors.initials: E
authors.lastname: Kim
authors.forename: Doyoon
authors.initials: D
authors.lastname: Kwon
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Yoon
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Shin
authors.forename: Eui-June
authors.initials: EJ
authors.lastname: Jeong
authors.forename: Sam Yong
authors.initials: SY
authors.lastname: Park
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Lee
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.forename: Seonggu
authors.initials: S
authors.lastname: Ro
authors.forename: Joong Myung
authors.initials: JM
authors.lastname: Cho
authors.forename: Kwang Yeon
authors.initials: KY
authors.lastname: Hwang
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; C000211:2-amino-3-phosphonopropionic acid; D012694:Serine; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D000409:Alanine