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Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR
Besides aiding digestion, bile salts are important signal molecules exhibiting a regulatory role in metabolic processes. Human ileal bile acid binding protein (I‐BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepa...
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Published in: | The FEBS journal 2016-02, Vol.283 (3), p.541-555 |
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description | Besides aiding digestion, bile salts are important signal molecules exhibiting a regulatory role in metabolic processes. Human ileal bile acid binding protein (I‐BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I‐BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I‐BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I‐BABP–bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I‐BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3. |
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Human ileal bile acid binding protein (I‐BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I‐BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I‐BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I‐BABP–bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I‐BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3.</description><identifier>ISSN: 1742-464X</identifier><identifier>EISSN: 1742-4658</identifier><identifier>DOI: 10.1111/febs.13610</identifier><identifier>PMID: 26613247</identifier><language>eng</language><publisher>England: Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies</publisher><subject>Bile ; bile acids ; bile salts ; binding proteins ; Binding Sites ; Carrier Proteins - chemistry ; conformational selection ; cooperativity ; digestion ; energy ; enterohepatic circulation ; epithelial cells ; Glycochenodeoxycholic Acid - chemistry ; Glycocholic Acid - chemistry ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; hydrophobic bonding ; ileum ; Ligands ; lipid binding proteins ; Magnetic Resonance Spectroscopy ; Membrane Glycoproteins - chemistry ; molecular recognition ; Molecular Structure ; nuclear magnetic resonance spectroscopy ; Proteins ; Rodents ; Solutions</subject><ispartof>The FEBS journal, 2016-02, Vol.283 (3), p.541-555</ispartof><rights>2015 FEBS</rights><rights>2015 FEBS.</rights><rights>Copyright © 2016 Federation of European Biochemical Societies</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4870-5e33cbefd054380557b3dba4f48e0f9a07d4bd7d8ae3ce728fd3fa06ba7fc3a83</citedby><cites>FETCH-LOGICAL-c4870-5e33cbefd054380557b3dba4f48e0f9a07d4bd7d8ae3ce728fd3fa06ba7fc3a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26613247$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Horváth, Gergő</creatorcontrib><creatorcontrib>Bencsura, Ákos</creatorcontrib><creatorcontrib>Simon, Ágnes</creatorcontrib><creatorcontrib>Tochtrop, Gregory P</creatorcontrib><creatorcontrib>DeKoster, Gregory T</creatorcontrib><creatorcontrib>Covey, Douglas F</creatorcontrib><creatorcontrib>Cistola, David P</creatorcontrib><creatorcontrib>Toke, Orsolya</creatorcontrib><title>Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR</title><title>The FEBS journal</title><addtitle>FEBS J</addtitle><description>Besides aiding digestion, bile salts are important signal molecules exhibiting a regulatory role in metabolic processes. Human ileal bile acid binding protein (I‐BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I‐BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I‐BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I‐BABP–bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I‐BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3.</description><subject>Bile</subject><subject>bile acids</subject><subject>bile salts</subject><subject>binding proteins</subject><subject>Binding Sites</subject><subject>Carrier Proteins - chemistry</subject><subject>conformational selection</subject><subject>cooperativity</subject><subject>digestion</subject><subject>energy</subject><subject>enterohepatic circulation</subject><subject>epithelial cells</subject><subject>Glycochenodeoxycholic Acid - chemistry</subject><subject>Glycocholic Acid - chemistry</subject><subject>Humans</subject><subject>Hydrogen Bonding</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>hydrophobic bonding</subject><subject>ileum</subject><subject>Ligands</subject><subject>lipid binding proteins</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Membrane Glycoproteins - chemistry</subject><subject>molecular recognition</subject><subject>Molecular Structure</subject><subject>nuclear magnetic resonance spectroscopy</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Solutions</subject><issn>1742-464X</issn><issn>1742-4658</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp9kd1qVDEUhQ-i2Fq98QE04I0UpiYnOX-XWtoqVAXHgnchPzszKTnJmOTQzmP5hmY8MxW8MDc7JN9abNaqqpcEn5Fy3hmQ6YzQluBH1THpWL1gbdM_frizH0fVs5RuMaYNG4an1VHdtoTWrDuufi1znFSeonBIQ4Y4Wi98TigY5OxKeI2k9dr6FbIe5TWgwngRt0iFcePgfgeup1F4ZB0UE1kGEsr-1W1iyFDEdzav0cptVVDr4EQuWHHfP4APGsL99vAVZBbWg0YmhhGl4KZsg0dfPn97Xj0xwiV4sZ8n1c3lxffzj4vrr1efzt9fLxTrO7xogFIlwWjcMNrjpukk1VIww3rAZhC400zqTvcCqIKu7o2mRuBWis4oKnp6Ur2dfcv-PydImY82KXBOeAhT4qRr66FtBlwX9M0_6G2YSkpuptqBkWYo1OlMqRhSimD4JtqxRMkJ5rsi-a5I_qfIAr_aW05yBP2AHporAJmBuxL49j9W_PLiw_Jg-nrWGBG4WEWb-M2yxqTFGPeYsIb-BpKjtqo</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Horváth, Gergő</creator><creator>Bencsura, Ákos</creator><creator>Simon, Ágnes</creator><creator>Tochtrop, Gregory P</creator><creator>DeKoster, Gregory T</creator><creator>Covey, Douglas F</creator><creator>Cistola, David P</creator><creator>Toke, Orsolya</creator><general>Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies</general><general>Blackwell Publishing Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201602</creationdate><title>Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR</title><author>Horváth, Gergő ; 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Human ileal bile acid binding protein (I‐BABP) is an intracellular carrier of bile salts in the epithelial cells of the distal small intestine and has a key role in the enterohepatic circulation of bile salts. Positive binding cooperativity combined with site selectivity of glycocholate and glycochenodeoxycholate, the two most abundant bile salts in the human body, make human I‐BABP a unique member of the family of intracellular lipid binding proteins. Solution NMR structure of the ternary complex of human I‐BABP with glycocholate and glycochenodeoxycholate reveals an extensive network of hydrogen bonds and hydrophobic interactions stabilizing the bound bile salts. Conformational changes accompanying bile salt binding affects four major regions in the protein including the C/D, E/F and G/H loops as well as the helical segment. Most of these protein regions coincide with a previously described network of millisecond time scale fluctuations in the apo protein, a motion absent in the bound state. Comparison of the heterotypic doubly ligated complex with the unligated form provides further evidence of a conformation selection mechanism of ligand entry. Structural and dynamic aspects of human I‐BABP–bile salt interaction are discussed and compared with characteristics of ligand binding in other members of the intracellular lipid binding protein family. PROTEIN DATA BANK ACCESSION NUMBERS: The coordinates of the 10 lowest energy structures of the human I‐BABP : GCDA : GCA complex as well as the distance restraints used to calculate the final ensemble have been deposited in the Brookhaven Protein Data Bank with accession number 2MM3.</abstract><cop>England</cop><pub>Published by Blackwell Pub. on behalf of the Federation of European Biochemical Societies</pub><pmid>26613247</pmid><doi>10.1111/febs.13610</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Bile bile acids bile salts binding proteins Binding Sites Carrier Proteins - chemistry conformational selection cooperativity digestion energy enterohepatic circulation epithelial cells Glycochenodeoxycholic Acid - chemistry Glycocholic Acid - chemistry Humans Hydrogen Bonding Hydrophobic and Hydrophilic Interactions hydrophobic bonding ileum Ligands lipid binding proteins Magnetic Resonance Spectroscopy Membrane Glycoproteins - chemistry molecular recognition Molecular Structure nuclear magnetic resonance spectroscopy Proteins Rodents Solutions |
title | Structural determinants of ligand binding in the ternary complex of human ileal bile acid binding protein with glycocholate and glycochenodeoxycholate obtained from solution NMR |
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