Assessment by molecular dynamics simulations of the structural determinants of DNA-binding specificity for transcription factor Sp1.
Identifieur interne : 003231 ( Main/Exploration ); précédent : 003230; suivant : 003232Assessment by molecular dynamics simulations of the structural determinants of DNA-binding specificity for transcription factor Sp1.
Auteurs : Esther Marco [Espagne] ; Raquel García-Nieto ; Federico GagoSource :
- Journal of molecular biology [ 0022-2836 ] ; 2003.
Descripteurs français
- KwdFr :
- ADN (), ADN (métabolisme), Adénine (métabolisme), Conformation d'acide nucléique, Conformation des protéines, Doigts de zinc, Données de séquences moléculaires, Facteur de transcription Sp1 (), Facteur de transcription Sp1 (génétique), Facteur de transcription Sp1 (métabolisme), Facteurs de transcription (génétique), Facteurs de transcription (métabolisme), Modèles moléculaires, Phosphates (), Phosphates (métabolisme), Protéines de liaison à l'ADN (génétique), Protéines de liaison à l'ADN (métabolisme), Régions promotrices (génétique), Simulation numérique, Spécificité du substrat, Structures macromoléculaires, Séquence d'acides aminés, Séquence nucléotidique.
- MESH :
- génétique : Facteur de transcription Sp1, Facteurs de transcription, Protéines de liaison à l'ADN.
- métabolisme : ADN, Adénine, Facteur de transcription Sp1, Facteurs de transcription, Phosphates, Protéines de liaison à l'ADN.
- ADN, Conformation d'acide nucléique, Conformation des protéines, Doigts de zinc, Données de séquences moléculaires, Facteur de transcription Sp1, Modèles moléculaires, Phosphates, Régions promotrices (génétique), Simulation numérique, Spécificité du substrat, Structures macromoléculaires, Séquence d'acides aminés, Séquence nucléotidique.
English descriptors
- KwdEn :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics), Adenine (metabolism), Amino Acid Sequence, Base Sequence, Computer Simulation, DNA (chemistry), DNA (metabolism), DNA-Binding Proteins (genetics), DNA-Binding Proteins (metabolism), Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Phosphates (chemistry), Phosphates (metabolism), Promoter Regions, Genetic, Protein Conformation, Sp1 Transcription Factor (chemistry), Sp1 Transcription Factor (genetics), Sp1 Transcription Factor (metabolism), Substrate Specificity, Transcription Factors (genetics), Transcription Factors (metabolism), Zinc Fingers.
- MESH :
- chemical , chemistry : DNA, Phosphates, Sp1 Transcription Factor.
- chemical , genetics : ATP Binding Cassette Transporter, Subfamily B, Member 1, DNA-Binding Proteins, Sp1 Transcription Factor, Transcription Factors.
- chemical , metabolism : Adenine, DNA, DNA-Binding Proteins, Phosphates, Sp1 Transcription Factor, Transcription Factors.
- Amino Acid Sequence, Base Sequence, Computer Simulation, Macromolecular Substances, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Promoter Regions, Genetic, Protein Conformation, Substrate Specificity, Zinc Fingers.
Abstract
The DNA-binding domain (DBD) of the ubiquituous transcription factor Sp1 consists of three consecutive zinc fingers that recognize a number of nucleotide sequences different from, but related to and sometimes overlapping, those recognized by the structurally better characterized early growth response protein 1 (EGR1, also known as Zif268, Krox-24, and NGFI-A). The accepted consensus binding sequence for Sp1 is usually defined by the asymmetric hexanucleotide core GGGCGG but this sequence does not include, among others, the GAG (=CTC) repeat that constitutes a high-affinity site for Sp1 binding to the wt1 promoter. Since no 3D structure of the whole DBD of Sp1 is available, either alone or in complex with DNA, a homology-based model was built and its interaction with two DNA 14-mers was studied using nanosecond molecular dynamics simulations in the presence of explicit water molecules. These oligonucleotides represent Sp1 target sites that are present in the promoters of the mdr1 and wt1 genes. For comparative purposes and validation of the protocol, the complex between the DBD of EGR1 and its DNA target site within the proximal mdr1 promoter was simulated under the same conditions. Some water molecules were seen to play an important role in recognition and stabilization of the protein-DNA complexes. Our results, which are supported by the available experimental evidence, suggest that the accuracy in the prediction of putative Sp1-binding sites can be improved by interpreting a set of rules, which are a blend of both stringency and tolerance, for the juxtaposed triplet subsites to which each zinc finger binds. Our approach can be extrapolated to WT1 and other related natural or artificial zinc-finger-containing DNA-binding proteins and may aid in the assignment of particular DNA stretches as allowed or disallowed-binding sites.
DOI: 10.1016/s0022-2836(03)00243-2
PubMed: 12683994
Affiliations:
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Le document en format XML
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Madrid</region></placeName></affiliation></author><author><name sortKey="Garcia Nieto, Raquel" sort="Garcia Nieto, Raquel" uniqKey="Garcia Nieto R" first="Raquel" last="García-Nieto">Raquel García-Nieto</name></author><author><name sortKey="Gago, Federico" sort="Gago, Federico" uniqKey="Gago F" first="Federico" last="Gago">Federico Gago</name></author></analytic><series><title level="j">Journal of molecular biology</title><idno type="ISSN">0022-2836</idno><imprint><date when="2003" type="published">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)</term><term>Adenine (metabolism)</term><term>Amino Acid Sequence</term><term>Base Sequence</term><term>Computer Simulation</term><term>DNA (chemistry)</term><term>DNA (metabolism)</term><term>DNA-Binding Proteins (genetics)</term><term>DNA-Binding Proteins (metabolism)</term><term>Macromolecular Substances</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>Phosphates (chemistry)</term><term>Phosphates (metabolism)</term><term>Promoter Regions, Genetic</term><term>Protein Conformation</term><term>Sp1 Transcription Factor (chemistry)</term><term>Sp1 Transcription Factor (genetics)</term><term>Sp1 Transcription Factor (metabolism)</term><term>Substrate Specificity</term><term>Transcription Factors (genetics)</term><term>Transcription Factors (metabolism)</term><term>Zinc Fingers</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN ()</term><term>ADN (métabolisme)</term><term>Adénine (métabolisme)</term><term>Conformation d'acide nucléique</term><term>Conformation des protéines</term><term>Doigts de zinc</term><term>Données de séquences moléculaires</term><term>Facteur de transcription Sp1 ()</term><term>Facteur de transcription Sp1 (génétique)</term><term>Facteur de transcription Sp1 (métabolisme)</term><term>Facteurs de transcription (génétique)</term><term>Facteurs de transcription (métabolisme)</term><term>Modèles moléculaires</term><term>Phosphates ()</term><term>Phosphates (métabolisme)</term><term>Protéines de liaison à l'ADN (génétique)</term><term>Protéines de liaison à l'ADN (métabolisme)</term><term>Régions promotrices (génétique)</term><term>Simulation numérique</term><term>Spécificité du substrat</term><term>Structures macromoléculaires</term><term>Séquence d'acides aminés</term><term>Séquence nucléotidique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>DNA</term><term>Phosphates</term><term>Sp1 Transcription Factor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>ATP Binding Cassette Transporter, Subfamily B, Member 1</term><term>DNA-Binding Proteins</term><term>Sp1 Transcription Factor</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adenine</term><term>DNA</term><term>DNA-Binding Proteins</term><term>Phosphates</term><term>Sp1 Transcription Factor</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Facteur de transcription Sp1</term><term>Facteurs de transcription</term><term>Protéines de liaison à l'ADN</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ADN</term><term>Adénine</term><term>Facteur de transcription Sp1</term><term>Facteurs de transcription</term><term>Phosphates</term><term>Protéines de liaison à l'ADN</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Base Sequence</term><term>Computer Simulation</term><term>Macromolecular Substances</term><term>Models, Molecular</term><term>Molecular Sequence Data</term><term>Nucleic Acid Conformation</term><term>Promoter Regions, Genetic</term><term>Protein Conformation</term><term>Substrate Specificity</term><term>Zinc Fingers</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>ADN</term><term>Conformation d'acide nucléique</term><term>Conformation des protéines</term><term>Doigts de zinc</term><term>Données de séquences moléculaires</term><term>Facteur de transcription Sp1</term><term>Modèles moléculaires</term><term>Phosphates</term><term>Régions promotrices (génétique)</term><term>Simulation numérique</term><term>Spécificité du substrat</term><term>Structures macromoléculaires</term><term>Séquence d'acides aminés</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The DNA-binding domain (DBD) of the ubiquituous transcription factor Sp1 consists of three consecutive zinc fingers that recognize a number of nucleotide sequences different from, but related to and sometimes overlapping, those recognized by the structurally better characterized early growth response protein 1 (EGR1, also known as Zif268, Krox-24, and NGFI-A). The accepted consensus binding sequence for Sp1 is usually defined by the asymmetric hexanucleotide core GGGCGG but this sequence does not include, among others, the GAG (=CTC) repeat that constitutes a high-affinity site for Sp1 binding to the wt1 promoter. Since no 3D structure of the whole DBD of Sp1 is available, either alone or in complex with DNA, a homology-based model was built and its interaction with two DNA 14-mers was studied using nanosecond molecular dynamics simulations in the presence of explicit water molecules. These oligonucleotides represent Sp1 target sites that are present in the promoters of the mdr1 and wt1 genes. For comparative purposes and validation of the protocol, the complex between the DBD of EGR1 and its DNA target site within the proximal mdr1 promoter was simulated under the same conditions. Some water molecules were seen to play an important role in recognition and stabilization of the protein-DNA complexes. Our results, which are supported by the available experimental evidence, suggest that the accuracy in the prediction of putative Sp1-binding sites can be improved by interpreting a set of rules, which are a blend of both stringency and tolerance, for the juxtaposed triplet subsites to which each zinc finger binds. Our approach can be extrapolated to WT1 and other related natural or artificial zinc-finger-containing DNA-binding proteins and may aid in the assignment of particular DNA stretches as allowed or disallowed-binding sites.</div></front></TEI><affiliations><list><country><li>Espagne</li></country><region><li>Communauté de Madrid</li></region><settlement><li>Madrid</li></settlement></list><tree><noCountry><name sortKey="Gago, Federico" sort="Gago, Federico" uniqKey="Gago F" first="Federico" last="Gago">Federico Gago</name><name sortKey="Garcia Nieto, Raquel" sort="Garcia Nieto, Raquel" uniqKey="Garcia Nieto R" first="Raquel" last="García-Nieto">Raquel García-Nieto</name></noCountry><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Marco, Esther" sort="Marco, Esther" uniqKey="Marco E" first="Esther" last="Marco">Esther Marco</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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