{"corpus_id":34070538,"paper_sha":"7c0c48d48b72c72891449826ec2d7bf5e866557a","doi":"10.1074/jbc.M409440200","arxiv_id":null,"pmid":15448133,"pmcid":null,"mag_id":2009218185,"dblp_id":null,"acl_id":null,"title":"Structural Basis of Biopterin-induced Inhibition of GTP Cyclohydrolase I by GFRP, Its Feedback Regulatory Protein*","year":2004,"publication_date":"2004-12-03","venue":"Journal of Biological Chemistry","journal":{"name":"Journal of Biological Chemistry","pages":"51534 - 51540","volume":"279"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't","Research Support, U.S. Gov't, P.H.S."],"s2_fields_of_study":["Biology","Medicine","Chemistry"],"reference_count":37,"citation_count":55,"influential_citation_count":7,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Amino Acid Sequence","mj":false,"ui":"D000595"},{"d":"Animals","mj":false,"ui":"D000818"},{"d":"Binding Sites","mj":false,"ui":"D001665"},{"d":"Biopterins","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"}],"ui":"D001708"},{"d":"Crystallography, X-Ray","mj":false,"ui":"D018360"},{"d":"Dihydroxyphenylalanine","mj":false,"qs":[{"q":"pharmacology","mj":false,"ui":"Q000494"}],"ui":"D004295"},{"d":"Escherichia coli","mj":false,"qs":[{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D004926"},{"d":"GTP Cyclohydrolase","mj":false,"qs":[{"q":"antagonists & inhibitors","mj":true,"ui":"Q000037"},{"q":"chemistry","mj":false,"ui":"Q000737"}],"ui":"D006136"},{"d":"Gene Expression Regulation","mj":false,"ui":"D005786"},{"d":"Intracellular Signaling Peptides and Proteins","mj":false,"ui":"D047908"},{"d":"Models, Molecular","mj":false,"ui":"D008958"},{"d":"Molecular Sequence Data","mj":false,"ui":"D008969"},{"d":"Mutation","mj":false,"ui":"D009154"},{"d":"Peptides","mj":false,"qs":[{"q":"chemistry","mj":false,"ui":"Q000737"}],"ui":"D010455"},{"d":"Phenylalanine","mj":false,"qs":[{"q":"chemistry","mj":false,"ui":"Q000737"}],"ui":"D010649"},{"d":"Protein Binding","mj":false,"ui":"D011485"},{"d":"Protein Conformation","mj":false,"ui":"D011487"},{"d":"Protein Structure, Secondary","mj":false,"ui":"D017433"},{"d":"Protein Structure, Tertiary","mj":false,"ui":"D017434"},{"d":"Proteins","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"}],"ui":"D011506"},{"d":"Rats","mj":false,"ui":"D051381"}],"chemicals":[{"n":"Gchfr protein, rat","ui":"C491065","reg":"0"},{"n":"Intracellular Signaling Peptides and Proteins","ui":"D047908","reg":"0"},{"n":"Peptides","ui":"D010455","reg":"0"},{"n":"Proteins","ui":"D011506","reg":"0"},{"n":"Biopterins","ui":"D001708","reg":"0"},{"n":"Phenylalanine","ui":"D010649","reg":"47E5O17Y3R"},{"n":"Dihydroxyphenylalanine","ui":"D004295","reg":"63-84-3"},{"n":"GTP Cyclohydrolase","ui":"D006136","reg":"EC 3.5.4.16"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"http://www.jbc.org/article/S0021925820694492/pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/7c0c48d48b72c72891449826ec2d7bf5e866557a","s2_open_access_license":"CCBY","s2_open_access_status":"HYBRID","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"GTP cyclohydrolase I (GTPCHI) is the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin, a key cofactor necessary for nitric oxide synthase and for the hydroxylases that are involved in the production of catecholamines and serotonin. In animals, the GTPCHI feedback regulatory protein (GFRP) binds GTPCHI to mediate feed-forward activation of GTPCHI activity in the presence of phenylalanine, whereas it induces feedback inhibition of enzyme activity in the presence of biopterin. Here, we have reported the crystal structure of the biopterin-induced inhibitory complex of GTPCHI and GFRP and compared it with the previously reported phenylalanine-induced stimulatory complex. The structure reveals five biopterin molecules located at each interface between GTPCHI and GFRP. Induced fitting structural changes by the biopterin binding expand large conformational changes in GTPCHI peptide segments forming the active site, resulting in inhibition of the activity. By locating 3,4-dihydroxy-phenylalanine-responsive dystonia mutations in the complex structure, we found mutations that may possibly disturb the GFRP-mediated regulation of GTPCHI.","claims":[{"public_id":"cl_a03ddad2f20ec2ed32e3c2ded3ffb746","status":"active","text":"Biopterin binding induces structural changes that expand conformational rearrangements in GTP cyclohydrolase I peptide segments forming the active site, leading to inhibition of enzyme activity.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_a03ddad2f20ec2ed32e3c2ded3ffb746"},{"public_id":"cl_da483bf8f4a055b71d31ddbf667dc945","status":"active","text":"Five biopterin molecules are located at each interface between GTP cyclohydrolase I and GTP cyclohydrolase I feedback regulatory protein.","confidence":0.94,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_da483bf8f4a055b71d31ddbf667dc945"},{"public_id":"cl_a2799acc3b6345a5f41de75cd61922e1","status":"active","text":"Some 3,4-dihydroxy-phenylalanine-responsive dystonia mutations may disturb GTP cyclohydrolase I regulation mediated by GTP cyclohydrolase I feedback regulatory protein.","confidence":0.85,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_a2799acc3b6345a5f41de75cd61922e1"},{"public_id":"cl_8e0ca70d99a7b35a1b7dda38b8732b84","status":"active","text":"The crystal structure of the biopterin-induced inhibitory complex of GTP cyclohydrolase I and GTP cyclohydrolase I feedback regulatory protein was determined and compared with the previously reported phenylalanine-induced stimulatory complex.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_8e0ca70d99a7b35a1b7dda38b8732b84"}],"concepts":[{"public_id":"co_13b777b3400e79c22f7f21f64e5816e0","status":"active","name":"active site","description":"The catalytic region of GTP cyclohydrolase I that undergoes conformational changes affecting enzyme activity.","types":["protein region"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_13b777b3400e79c22f7f21f64e5816e0"},{"public_id":"co_3f12072bf944e9317ffb90d720668859","status":"active","name":"3,4-dihydroxy-phenylalanine-responsive dystonia mutations","description":"Disease-associated mutations mapped onto the complex structure to assess their possible effects on regulation.","types":["mutation"],"aliases":["DOPA-responsive dystonia mutations"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_3f12072bf944e9317ffb90d720668859"},{"public_id":"co_60a5b1be30d65e672e10535b3cb71811","status":"active","name":"GTP cyclohydrolase I feedback regulatory protein","description":"A regulatory protein that binds GTP cyclohydrolase I to modulate its activity in response to effectors.","types":["regulatory protein"],"aliases":["GFRP"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_60a5b1be30d65e672e10535b3cb71811"},{"public_id":"co_6cf7e5816af99c7a314d74542541f903","status":"active","name":"tetrahydrobiopterin","description":"A key cofactor required for nitric oxide synthase and hydroxylases involved in catecholamine and serotonin production.","types":["cofactor"],"aliases":["BH4"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_6cf7e5816af99c7a314d74542541f903"},{"public_id":"co_781049116650bee82e6eee7c86eb9769","status":"active","name":"GTP cyclohydrolase I","description":"The rate-limiting enzyme in tetrahydrobiopterin biosynthesis.","types":["enzyme"],"aliases":["GTPCHI"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_781049116650bee82e6eee7c86eb9769"},{"public_id":"co_c274025b088e31a88a40f9a32fb95a95","status":"active","name":"phenylalanine","description":"An amino acid that promotes feed-forward activation of GTP cyclohydrolase I through GTP cyclohydrolase I feedback regulatory protein.","types":["metabolite"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_c274025b088e31a88a40f9a32fb95a95"},{"public_id":"co_e7a032d420ce3df4c3e6ceb72a402ab3","status":"active","name":"biopterin-induced inhibitory complex","description":"The protein complex formed by GTP cyclohydrolase I and GTP cyclohydrolase I feedback regulatory protein in the biopterin-bound inhibitory state.","types":["protein complex"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_e7a032d420ce3df4c3e6ceb72a402ab3"},{"public_id":"co_eef938f16a5c518585abf385ad2c56d5","status":"active","name":"phenylalanine-induced stimulatory complex","description":"The protein complex formed by GTP cyclohydrolase I and GTP cyclohydrolase I feedback regulatory protein in the phenylalanine-bound activating state.","types":["protein complex"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_eef938f16a5c518585abf385ad2c56d5"},{"public_id":"co_f8898a5e105c188f1272be7d6b84138f","status":"active","name":"biopterin","description":"A pterin effector that induces feedback inhibition of GTP cyclohydrolase I through GTP cyclohydrolase I feedback regulatory protein.","types":["metabolite"],"aliases":[],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_f8898a5e105c188f1272be7d6b84138f"}],"external_ids":{"DOI":"10.1074/jbc.M409440200","ArXiv":null,"PubMed":15448133,"PubMedCentral":null,"MAG":2009218185,"DBLP":null,"ACL":null},"open_access":{"is_open_access":true,"pdf_url":"http://www.jbc.org/article/S0021925820694492/pdf","landing_url":"https://www.semanticscholar.org/paper/7c0c48d48b72c72891449826ec2d7bf5e866557a","source":"semantic_scholar","pdf_url_source":"semantic_scholar_open_access_pdf","license":"CCBY","status":"HYBRID","reason":null},"reference_availability":{"status":"available","references_indexed":true,"full_text_available":false,"full_text_source":null,"count_basis":"semantic_scholar_metadata","extraction_status":"not_applicable","reason":null},"source":{"provider":"episteme2","base_corpus":"semantic_scholar_dump","freshness_mode":"unknown","basis":["semantic_scholar_metadata","postgres_metadata"],"limits":["paper metadata is based on indexed upstream scholarly datasets","claims and concepts are available only for extracted papers","absence of claims or concepts means no extracted graph data is available in this response"],"status":"available","degraded":false,"degraded_reasons":[],"diagnostics":{"status":"available","degraded":false,"degraded_reasons":[],"metadata_status":"available","graph_status":"available","abstract_status":"available"},"source_flags":5},"paper_id":633333,"paper_uid":"8e4a29f8-235b-4cfc-b98c-c7bb54a0dd07","canonical_identity":{"paper_id":633333,"paper_uid":"8e4a29f8-235b-4cfc-b98c-c7bb54a0dd07","identity_status":"available","lookup_basis":"semantic_scholar_external_id","compatibility_path":"corpus_id"},"url":"https://sah.borca.ai/papers/34070538"}