The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP

Eads, Janina C.; Scapin, Giovanna; Xu, Yiming; Grubmeyer, Charles; Sacchettini, James C.

doi:10.1016/0092-8674(94)90301-8

Cited by 222 publications

(334 citation statements)

References 39 publications

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“…33 In APRT (as in other purine and pyrimidine phosphoribosyltransferases), the base of the nucleoside monophosphate reaction product is sandwiched between an aromatic residue providing π-π stacking on one face and a leucine (or isoleucine) residue on the other, with a hydroxyl group coordinated via a carboxylate side-chain ( Figure 6(c)). 32,40 In all three systems, the residues that contribute to these sites are highly conserved; however, their sequence contexts are distinct. Thus, in APRT, the Glu/Leu pair are neighbors in the highly conserved PRT signature motif, 41 while the aromatic residue (here Phe26) is from a separate domain.…”

Section: Gmp Is Bound On the Surface Of The Gtpase Heterodimer At A Cmentioning

confidence: 99%

“…Such interactions are common to nucleotide-binding proteins; anionic interaction with a nucleotide hydroxyl group, [30][31][32] and aromatic stacking against a nucleotide base occur in the DNA repair enzymes, 33,34 γ-tubulin, 35 the U1A spliceosomal protein, 36 the purine and pyrimidine phosphoribosyltransferases 32,37 and aspartyl-tRNA synthetase. 38 Indeed, the binding configuration at the SRP GTPase external nucleotide site is specifically reminiscent of similar arrangements in crystal structures of the editing complex of Klenow fragment 34,39 and AMP-bound adenine phosphoribosyltransferase (APRT) 40 ( Figure 6).…”

Section: Gmp Is Bound On the Surface Of The Gtpase Heterodimer At A Cmentioning

confidence: 99%

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Structure of a GDP:AlF4 Complex of the SRP GTPases Ffh and FtsY, and Identification of a Peripheral Nucleotide Interaction Site

Focia

Gawronski-Salerno

Coon

et al. 2006

Journal of Molecular Biology

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The signal recognition particle (SRP) GTPases Ffh and FtsY play a central role in co-translational targeting of proteins, assembling in a GTP-dependent manner to generate the SRP targeting complex at the membrane. A suite of residues in FtsY have been identified that are essential for the hydrolysis of GTP that accompanies disengagement. We have argued previously on structural grounds that this region mediates interactions that serve to activate the complex for disengagement and term it the activation region. We report here the structure of a complex of the SRP GTPases formed in the presence of GDP:AlF 4 . This complex accommodates the putative transition-state analog without undergoing significant change from the structure of the ground-state complex formed in the presence of the GTP analog GMPPCP. However, small shifts that do occur within the shared catalytic chamber may be functionally important. Remarkably, an external nucleotide interaction site was identified at the activation region, revealed by an unexpected contaminating GMP molecule bound adjacent to the catalytic chamber. This site exhibits conserved sequence and structural features that suggest a direct interaction with RNA plays a role in regulating the activity of the SRP targeting complex.

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Section: Gmp Is Bound On the Surface Of The Gtpase Heterodimer At A Cmentioning

confidence: 99%

Section: Gmp Is Bound On the Surface Of The Gtpase Heterodimer At A Cmentioning

confidence: 99%

Structure of a GDP:AlF4 Complex of the SRP GTPases Ffh and FtsY, and Identification of a Peripheral Nucleotide Interaction Site

Focia

Gawronski-Salerno

Coon

et al. 2006

Journal of Molecular Biology

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“…Yet, the carboxyl-modifying reagent ethyl dimethylaminopropyl carbodiimide did not inactivate the protein. From the three-dimensional structures of HG(X)PRT proteins, it has been suggested that this Glu-Asp dipeptide functions in the binding of the ribose moiety of PRPP via a Mg 2ϩ bridge and in the stabilization of the transition state complex (4,9). It is possible that the free carboxyl moieties in the Glu-Asp dipeptide are shielded from chemical modification by either coordination to Mg 2ϩ ions or by formation of internal salt bridges.…”

Section: -Fold (28)mentioning

confidence: 99%

“…Several of these motifs are embedded within the core of the protein and may not be accessible to chemical modifying reagents (4). The Glu-Asp dipeptide that is situated within the PRPP binding motif that is found among all PRT family members (35) is, however, surface-exposed (4,5,9). Yet, the carboxyl-modifying reagent ethyl dimethylaminopropyl carbodiimide did not inactivate the protein.…”

Section: -Fold (28)mentioning

confidence: 99%

The Conserved Serine-Tyrosine Dipeptide in Leishmania donovani Hypoxanthine-guanine Phosphoribosyltransferase Is Essential for Catalytic Activity

Jardim

Ullman

1997

Journal of Biological Chemistry

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Protozoan parasites constitute a devastating public health and socioeconomic burden in the tropical and subtropical regions of the world. In the absence of effective vaccines, empirically derived drugs are the only means available to treat parasitic infections. However, the current arsenal of antiparasitic drugs is far from ideal, as these agents are moderately to highly toxic, possibly mutagenic and/or carcinogenic, and require protracted treatment regimens. The control of parasitic diseases has also been complicated by the emergence of drugresistant strains (1), further underscoring the need for novel antiparasitic agents. Rational development of new drugs that selectively target protozoan pathogens requires the exploitation of biochemical or metabolic differences between parasite and host. As protozoan parasites, unlike mammalian cells, are auxotrophic for purines and consequently rely on purine appropriation from the host for survival and proliferation (2), the purine salvage pathway has stimulated considerable interest as a paradigm for antiparasitic drug development. One enzyme that is central to purine acquisition in many parasites (2) is hypoxanthine-guanine phosphoribosyltransferase (HGPRT) 1 which catalyzes the phosphoribosylpyrophosphate (PRPP)-dependent phosphoribosylation of hypoxanthine and guanine to the nucleotide level. In some parasites, HGPRT also recognizes xanthine as a substrate (3) and is, therefore, termed a hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGX-PRT). Genes and cDNAs encoding HG(X)PRT (HG(X)PRT) from a number of protozoan parasites have now been cloned, sequenced, and overexpressed in Escherichia coli, and the recombinant HG(X)PRT enzymes have been purified and characterized kinetically (3). Multisequence alignments demonstrate several short regions of amino acid homology among HG(X)-PRT family members that are flanked by much longer regions without significant sequence similarity. The crystal structures for the product-bound form of the human HGPRT (4) and the Tritrichomonas foetus HGXPRT (5) have revealed, however, a common core framework within the tertiary structure that is conserved among other members of the phosphoribosyltransferase (PRT) family (6 -8). These structures have established functional roles for all of the conserved regions in HG(X)PRT proteins, except one motif that is located on a flexible loop distal to the active site. This flexible loop encompasses a SerTyr dipeptide that is found in all HG(X)PRTs for which sequence is available. The recently determined crystal structures of the HGXPRT from Toxoplasma gondii in the absence of ligand and in the presence of product have demonstrated that this flexible loop in the apoenzyme is shifted toward the active

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“…Weare nowable to comparethose abnormalities with the site of the amino acid substitution in a 3D molecular structure. Thus human HPRTwas co-crystallized with GMP and from the X-ray refraction analysis, the 3D structure was elucidated (6). Whenwe plot the amino acid substitutions in both Lesch-Nyhan syndrome and partial HPRTdeficiency, they tend to accumulate in the portions which are structurally close to the product GMPalthough some exceptions are present.…”

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confidence: 99%

Partial Hypoxanthine Phosphoribosyltransferase Deficiency: Unrecognized Until Adult Ages

Kamatani

1998

Intern. Med.

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Hypoxanthine phosphoribosyltransferase (HPRT) is a purine metabolic enzymewhich converts hypoxanthineor guanine into IMP or GMP.One of the interesting viewpoints of HPRT deficiency is that there are two types of clinical features caused by the genetic enzyme deficiency ( 1 and 2 forreview). Thus, the severe type of the disease designated Lesch-Nyhan' s syndrome is associated with hyperuricemia and severe neuropsychological disorders characterized by a self mutilation behavior. The other milder type which is usually designated partial HPRT deficiency is associated with hyperuricemia but not with severe neuropsychological symptoms. The patients with LeschNyhan' s syndrome are usually discovered and taken care of by pediatricians, but recent extensive care has enabled the patients to grow up to over 16 years old and are observed by general physicians.

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The crystal structure of human hypoxanthine-guanine phosphoribosyltransferase with bound GMP

Cited by 222 publications

References 39 publications

Structure of a GDP:AlF4 Complex of the SRP GTPases Ffh and FtsY, and Identification of a Peripheral Nucleotide Interaction Site

Structure of a GDP:AlF4 Complex of the SRP GTPases Ffh and FtsY, and Identification of a Peripheral Nucleotide Interaction Site

The Conserved Serine-Tyrosine Dipeptide in Leishmania donovani Hypoxanthine-guanine Phosphoribosyltransferase Is Essential for Catalytic Activity

Partial Hypoxanthine Phosphoribosyltransferase Deficiency: Unrecognized Until Adult Ages

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