Crystal structure of the ternary complex of mouse lung carbonyl reductase at 1.8 å resolution: the structural origin of coenzyme specificity in the short-chain dehydrogenase/reductase family

Tanaka, Nobutada; Nonaka, Takamasa; Nakanishi, Mahito; Deyashiki, Yoshihiro; Hara, Akira; Mitsui, Yukio

doi:10.1016/s0969-2126(96)00007-x

Cited by 209 publications

(235 citation statements)

References 60 publications

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“…This represents an exception to the observation that basic amino acids close to the 2 0 -phosphate group determinate the preference of SDR enzymes for the nucleotide cofactor. 19 No basic residue is found close to the expected position in our present structure, whereas in other NADP þ -dependent SDR enzymes, there are two basic residues (Lys and Arg) close to the 2 0 -phosphate group in mouse lung carbonyl reductase (MLCR) 13 and glucose dehydrogenase (GlcDH) 19 and one in 1,3,8-trihydroxynaphthalene reductase (THNR). 18 The high Fo À Fc density peak (>6.6 r) close to the substrate was assigned for metal ion (see Fig.…”

Section: Oligomeric Assembly and Intersubunit Contactsmentioning

confidence: 45%

“…Like other NADP þ -dependent enzymes of the SDR family, 13,18 NADP þ molecules in the Ga5DH quaternary complex, Figure 2. Cartoon diagram of the Ga5DH subunit of S. suis.…”

Section: Oligomeric Assembly and Intersubunit Contactsmentioning

confidence: 99%

“…This latter finding contrasts with previous suggestions that the Ser and Tyr residues targeted the same axial carbon. 13 The residues Arg104 and Ser150 are therefore important determinants in the recognition and binding of substrate. The orientation of the C5 of the substrate is toward the C4 of the nicotinamide ring, and the distance of 4.1 Å is favorable to the subsequent hydride transfer between them.…”

Section: Comparison With Other Ga5dhsmentioning

confidence: 99%

“…Consequently, no structural information for any Ga5DH is currently available to permit elucidation of the molecular architecture or clarification of the catalytic mechanism of the enzyme. Within the SDR family, the ternary complex structures with bound product or substrate analog and NAD(P) þ reveal a cofactor binding domain, [11][12][13] Ser-Tyr-Lys catalytic triad, and a putative mechanism. 14,15 Although the roles of tyrosine and lysine have been established, a functional assignment to the serine residue of this triad has proven elusive.…”

Section: Introductionmentioning

confidence: 99%

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Structural insight into the catalytic mechanism of gluconate 5‐dehydrogenase from Streptococcus suis: Crystal structures of the substrate‐free and quaternary complex enzymes

Zhang¹,

Peng²,

Gao³

et al. 2009

Protein Science

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Gluconate 5-dehydrogenase (Ga5DH) is an NADP(H)-dependent enzyme that catalyzes a reversible oxidoreduction reaction between D-gluconate and 5-keto-D-gluconate, thereby regulating the flux of this important carbon and energy source in bacteria. Despite the considerable amount of physiological and biochemical knowledge of Ga5DH, there is little physical or structural information available for this enzyme. To this end, we herein report the crystal structures of Ga5DH from pathogenic Streptococcus suis serotype 2 in both substrate-free and liganded (NADP 1 /Dgluconate/metal ion) quaternary complex forms at 2.0 Å resolution. Structural analysis reveals that Ga5DH adopts a protein fold similar to that found in members of the short chain dehydrogenase/ reductase (SDR) family, while the enzyme itself represents a previously uncharacterized member of this family. In solution, Ga5DH exists as a tetramer that comprised four identical $29 kDa subunits. The catalytic site of Ga5DH shows considerable architectural similarity to that found in other enzymes of the SDR family, but the S. suis protein contains an additional residue (Arg104) that plays an important role in the binding and orientation of substrate. The quaternary complex structure provides the first clear crystallographic evidence for the role of a catalytically important serine residue and also reveals an amino acid tetrad RSYK that differs from the SYK triad found in the majority of SDR enzymes. Detailed analysis of the crystal structures reveals important contributions of Ca 21 ions to active site formation and of specific residues at the C-termini of subunits to tetramer assembly. Because Ga5DH is a potential target for therapy, our findings Additional Supporting Information may be found in the online version of this article. provide insight not only of catalytic mechanism, but also suggest a target of structure-based drug design.

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Section: Oligomeric Assembly and Intersubunit Contactsmentioning

confidence: 45%

“…Like other NADP þ -dependent enzymes of the SDR family, 13,18 NADP þ molecules in the Ga5DH quaternary complex, Figure 2. Cartoon diagram of the Ga5DH subunit of S. suis.…”

Section: Oligomeric Assembly and Intersubunit Contactsmentioning

confidence: 99%

Section: Comparison With Other Ga5dhsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural insight into the catalytic mechanism of gluconate 5‐dehydrogenase from Streptococcus suis: Crystal structures of the substrate‐free and quaternary complex enzymes

Zhang¹,

Peng²,

Gao³

et al. 2009

Protein Science

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“…Other SDR enzymes feature NADH for the catalytic process and early studies annotated this cofactor to the reductive direction of 17b-HSD1 30,41,42 . Numerous in vitro inhibition tests have been performed with supplementation of the unphosphorylated cofactor too.…”

Section: Cofactor Dependencementioning

confidence: 99%

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Herman

Szabó

Bacsa

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17b-hydroxysteroid dehydrogenase type 1 isozyme (17b-HSD1) were investigated. The transformation of estrone to 17b-estradiol was studied by an in vitro radiosubstrate incubation method. 13a-Estrone inhibited the enzyme activity effectively with an IC 50 value of 1.2 mM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13b derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13a and 3-ether counterparts. The 3-hydroxy13b-D-secoalcohol and the 3-hydroxy-13a-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy13b-D-secooxime has an IC 50 value of 0.070 mM and is one of the most effective 17b-HSD1 inhibitors reported to date in the literature.

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Structural trees for protein superfamilies

Ефимов

1997

Proteins

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Structural trees for large protein superfamilies, such as beta proteins with the aligned beta sheet packing, beta proteins with the orthogonal packing of alpha helices, two-layer and three-layer alpha/beta proteins, have been constructed. The structural motifs having unique overall folds and a unique handedness are taken as root structures of the trees. The larger protein structures of each superfamily are obtained by a stepwise addition of alpha helices and/or beta strands to the corresponding root motif, taking into account a restricted set of rules inferred from known principles of the protein structure. Among these rules, prohibition of crossing connections, attention to handedness and compactness, and a requirement for alpha helices to be packed in alpha-helical layers and beta strands in beta layers are the most important. Proteins and domains whose structures can be obtained by stepwise addition of alpha helices and/or beta strands to the same root motif can be grouped into one structural class or a superfamily. Proteins and domains found within branches of a structural tree can be grouped into subclasses or subfamilies. Levels of structural similarity between different proteins can easily be observed by visual inspection. Within one branch, protein structures having a higher position in the tree include the structures located lower. Proteins and domains of different branches have the structure located in the branching point as the common fold.

show abstract

Crystal structure of the ternary complex of mouse lung carbonyl reductase at 1.8 å resolution: the structural origin of coenzyme specificity in the short-chain dehydrogenase/reductase family

Cited by 209 publications

References 60 publications

Structural insight into the catalytic mechanism of gluconate 5‐dehydrogenase from Streptococcus suis: Crystal structures of the substrate‐free and quaternary complex enzymes

Structural insight into the catalytic mechanism of gluconate 5‐dehydrogenase from Streptococcus suis: Crystal structures of the substrate‐free and quaternary complex enzymes

Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Structural trees for protein superfamilies

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