Molecular basis for the local conformational rearrangement of human phosphoserine phosphatase.
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.
Kim
Hye-Yeon
HY
Divison of Drug Discovery, CrystalGenomics Incorporated, Daeduck Biocommunity, Jeonmin-dong, Yuseong-gu, Taejeon City, South Korea 305-600.
Heo
Yong-Seok
YS
Kim
Jin Hwan
JH
Park
Min Hye
MH
Moon
Jinho
J
Kim
Eunmi
E
Kwon
Doyoon
D
Yoon
Jeongmin
J
Shin
Dongkyu
D
Jeong
Eui-June
EJ
Park
Sam Yong
SY
Lee
Tae Gyu
TG
Jeon
Young Ho
YH
Ro
Seonggu
S
Cho
Joong Myung
JM
Hwang
Kwang Yeon
KY
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
D004791:Enzyme Inhibitors; C000211:2-amino-3-phosphonopropionic acid; D012694:Serine; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D000409:Alanine