1a4i

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(New page: 200px<br /> <applet load="1a4i" size="450" color="white" frame="true" align="right" spinBox="true" caption="1a4i, resolution 1.5&Aring;" /> '''HUMAN TETRAHYDROFOLA...)
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'''HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE'''<br />
'''HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE'''<br />
==Overview==
==Overview==
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BACKGROUND: The interconversion of two major folate one-carbon donors, occurs through the sequential activities of NAD(P)-dependent, methylene[H4]folate dehydrogenase (D) and methenyl[H4]folate, cyclohydrolase (C). These activities often coexist as part of a, multifunctional enzyme and there are several lines of evidence suggesting, that their substrates bind at overlapping sites. Little is known, however, about the nature of this site or the identity of the active-site residues, for this enzyme family. RESULTS: We have determined, to 1.5 A resolution, the structure of a dimer of the D/C domain of the human trifunctional, cytosolic enzyme with bound NADP cofactor, using the MAD technique. The, D/C subunit is composed of two alpha/beta domains that assemble to form a, wide cleft. The cleft walls are lined with highly conserved residues and, NADP is bound along one wall. The NADP-binding domain has a Rossmann fold, characterized by a modified diphosphate-binding loop fingerprint-GXSXXXG., Dimerization occurs by antiparallel interaction of two NADP-binding, domains. Superposition of the two subunits indicates domain motion occurs, about a well-defined hinge region. CONCLUSIONS: Analysis of the structure, suggests strongly that folate-binding sites for both activities are within, the cleft, providing direct support for the proposed overlapping site, model. The orientation of the nicotinamide ring suggests that in the, dehydrogenase-catalyzed reaction hydride transfer occurs to the pro-R side, of the ring. The identity of the cyclohydrolase active site is not, obvious. We propose that a conserved motif-Tyr52-X-X-X-Lys56- and/or a, Ser49-Gln100-Pro102 triplet have a role in this activity.
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BACKGROUND: The interconversion of two major folate one-carbon donors occurs through the sequential activities of NAD(P)-dependent methylene[H4]folate dehydrogenase (D) and methenyl[H4]folate cyclohydrolase (C). These activities often coexist as part of a multifunctional enzyme and there are several lines of evidence suggesting that their substrates bind at overlapping sites. Little is known, however, about the nature of this site or the identity of the active-site residues for this enzyme family. RESULTS: We have determined, to 1.5 A resolution, the structure of a dimer of the D/C domain of the human trifunctional cytosolic enzyme with bound NADP cofactor, using the MAD technique. The D/C subunit is composed of two alpha/beta domains that assemble to form a wide cleft. The cleft walls are lined with highly conserved residues and NADP is bound along one wall. The NADP-binding domain has a Rossmann fold, characterized by a modified diphosphate-binding loop fingerprint-GXSXXXG. Dimerization occurs by antiparallel interaction of two NADP-binding domains. Superposition of the two subunits indicates domain motion occurs about a well-defined hinge region. CONCLUSIONS: Analysis of the structure suggests strongly that folate-binding sites for both activities are within the cleft, providing direct support for the proposed overlapping site model. The orientation of the nicotinamide ring suggests that in the dehydrogenase-catalyzed reaction hydride transfer occurs to the pro-R side of the ring. The identity of the cyclohydrolase active site is not obvious. We propose that a conserved motif-Tyr52-X-X-X-Lys56- and/or a Ser49-Gln100-Pro102 triplet have a role in this activity.
==Disease==
==Disease==
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==About this Structure==
==About this Structure==
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1A4I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NDP as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1A4I OCA].
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1A4I is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=NDP:'>NDP</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1A4I OCA].
==Reference==
==Reference==
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[[Category: Cygler, M.]]
[[Category: Cygler, M.]]
[[Category: Li, Y.]]
[[Category: Li, Y.]]
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[[Category: Mackenzie, R.E.]]
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[[Category: Mackenzie, R E.]]
[[Category: NDP]]
[[Category: NDP]]
[[Category: bifunctional]]
[[Category: bifunctional]]
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[[Category: thf]]
[[Category: thf]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:40:51 2008''

Revision as of 09:40, 21 February 2008

Image:1a4i.gif

1a4i, resolution 1.5Å

Drag the structure with the mouse to rotate

HUMAN TETRAHYDROFOLATE DEHYDROGENASE / CYCLOHYDROLASE

Contents

Overview

BACKGROUND: The interconversion of two major folate one-carbon donors occurs through the sequential activities of NAD(P)-dependent methylene[H4]folate dehydrogenase (D) and methenyl[H4]folate cyclohydrolase (C). These activities often coexist as part of a multifunctional enzyme and there are several lines of evidence suggesting that their substrates bind at overlapping sites. Little is known, however, about the nature of this site or the identity of the active-site residues for this enzyme family. RESULTS: We have determined, to 1.5 A resolution, the structure of a dimer of the D/C domain of the human trifunctional cytosolic enzyme with bound NADP cofactor, using the MAD technique. The D/C subunit is composed of two alpha/beta domains that assemble to form a wide cleft. The cleft walls are lined with highly conserved residues and NADP is bound along one wall. The NADP-binding domain has a Rossmann fold, characterized by a modified diphosphate-binding loop fingerprint-GXSXXXG. Dimerization occurs by antiparallel interaction of two NADP-binding domains. Superposition of the two subunits indicates domain motion occurs about a well-defined hinge region. CONCLUSIONS: Analysis of the structure suggests strongly that folate-binding sites for both activities are within the cleft, providing direct support for the proposed overlapping site model. The orientation of the nicotinamide ring suggests that in the dehydrogenase-catalyzed reaction hydride transfer occurs to the pro-R side of the ring. The identity of the cyclohydrolase active site is not obvious. We propose that a conserved motif-Tyr52-X-X-X-Lys56- and/or a Ser49-Gln100-Pro102 triplet have a role in this activity.

Disease

Known diseases associated with this structure: Abruptio placentae, susceptibility to OMIM:[172460], Spina bifida, folate-sensitive, susceptibility to OMIM:[172460]

About this Structure

1A4I is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.

Reference

The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution., Allaire M, Li Y, MacKenzie RE, Cygler M, Structure. 1998 Feb 15;6(2):173-82. PMID:9519408

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