2h08 | pdb_00002h08
crystal structure of human phosphoribosyl pyrophosphate synthetase 1 mutant Y146M
Structural highlights
DiseasePRPS1_HUMAN Defects in PRPS1 are the cause of phosphoribosylpyrophosphate synthetase superactivity (PRPS1 superactivity) [MIM:300661; also known as PRPS-related gout. It is a familial disorder characterized by excessive purine production, gout and uric acid urolithiasis. Defects in PRPS1 are the cause of Charcot-Marie-Tooth disease X-linked recessive type 5 (CMTX5) [MIM:311070; also known as optic atrophy-polyneuropathy-deafness or Rosenberg-Chutorian syndrome. CMTX5 is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy.[1] Defects in PRPS1 are the cause of ARTS syndrome (ARTS) [MIM:301835; also known as fatal ataxia X-linked with deafness and loss of vision. ARTS is a disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Susceptibility to infections, especially of the upper respiratory tract, can result in early death.[2] Defects in PRPS1 are the cause of deafness X-linked type 1 (DFNX1) [MIM:304500; also known as congenital sensorineural deafness X-linked 2 (DFN2). It is a form of deafness characterized by progressive, severe-to-profound sensorineural hearing loss in males. Females manifest mild to moderate hearing loss.[3] FunctionPRPS1_HUMAN Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedPRPP (phosphoribosylpyrophosphate) is an important metabolite essential for nucleotide synthesis and PRS (PRPP synthetase) catalyses synthesis of PRPP from R5P (ribose 5-phosphate) and ATP. The enzymatic activity of PRS is regulated by phosphate ions, divalent metal cations and ADP. In the present study we report the crystal structures of recombinant human PRS1 in complexes with SO4(2-) ions alone and with ATP, Cd2+ and SO4(2-) ions respectively. The AMP moiety of ATP binds at the ATP-binding site, and a Cd2+ ion binds at the active site and in a position to interact with the beta- and gamma-phosphates of ATP. A SO4(2-) ion, an analogue of the activator phosphate, was found to bind at both the R5P-binding site and the allosteric site defined previously. In addi-tion, an extra SO4(2-) binds at a site at the dimer interface between the ATP-binding site and the allosteric site. Binding of this SO4(2-) stabilizes the conformation of the flexible loop at the active site, leading to the formation of the active, open conformation which is essential for binding of ATP and initiation of the catalytic reaction. This is the first time that structural stabilization at the active site caused by binding of an activator has been observed. Structural and biochemical data show that mutations of some residues at this site influence the binding of SO4(2-) and affect the enzymatic activity. The results in the present paper suggest that this new SO4(2-)-binding site is a second allosteric site to regulate the enzymatic activity which might also exist in other eukaryotic PRSs (except plant PRSs of class II), but not in bacterial PRSs. Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals a novel allosteric site.,Li S, Lu Y, Peng B, Ding J Biochem J. 2007 Jan 1;401(1):39-47. PMID:16939420[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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