Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy
Dihydrofolate reductase (DHFR) is an intracellular target enzyme for folate antagonist drugs, including methotrexatte. In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation o...
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| Veröffentlicht in: | FEBS letters 1991-06, Vol.283 (2), p.267-269 |
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| container_title | FEBS letters |
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| creator | Stockman, Brian J. Nirmala, N.R. Wagner, Gerhard Delcamp, Tavner J. DeYarman, Michael T. Freisheim, James H. |
| description | Dihydrofolate reductase (DHFR) is an intracellular target enzyme for folate antagonist drugs, including methotrexatte. In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation of the drug bound to human DHFR in solution. In agreement with what has been observed in the crystalline state, NOE's identified protein and methotrexate protons indicate that methotrexate binds in a non-productive orientation. In contrast to what has been reported for E. coli DHFR in solution, only one bound conformation of methotrexate is observed. |
| doi_str_mv | 10.1016/0014-5793(91)80604-2 |
| format | Article |
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In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation of the drug bound to human DHFR in solution. In agreement with what has been observed in the crystalline state, NOE's identified protein and methotrexate protons indicate that methotrexate binds in a non-productive orientation. In contrast to what has been reported for E. coli DHFR in solution, only one bound conformation of methotrexate is observed.</description><identifier>ISSN: 0014-5793</identifier><identifier>EISSN: 1873-3468</identifier><identifier>DOI: 10.1016/0014-5793(91)80604-2</identifier><identifier>PMID: 2044765</identifier><identifier>CODEN: FEBLAL</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Binding Sites ; Biological and medical sciences ; DHFR ; dihydrofolate reductase ; Dihydrofolate reductase, Protein NMR, Protein-drug interaction ; double quantum filtered correlated spectroscopy ; DQF-COSY ; Fundamental and applied biological sciences. Psychology ; Humans ; Interactions. Associations ; Intermolecular phenomena ; Magnetic Resonance Spectroscopy - methods ; Methotrexate ; Methotrexate - metabolism ; Molecular biophysics ; NOE ; NOESY ; nuclear Overhauser enhancement ; nuclear Overhauser enhancement spectroscopy ; Protein Binding ; Protein Conformation ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Solutions ; Tetrahydrofolate Dehydrogenase - chemistry ; Tetrahydrofolate Dehydrogenase - metabolism</subject><ispartof>FEBS letters, 1991-06, Vol.283 (2), p.267-269</ispartof><rights>1991</rights><rights>FEBS Letters 283 (1991) 1873-3468 © 2015 Federation of European Biochemical Societies</rights><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4422-c0cfd4a55d11f3f205f87196646a6baa4381b223788163b13f98ce7e2cc2d7943</citedby><cites>FETCH-LOGICAL-c4422-c0cfd4a55d11f3f205f87196646a6baa4381b223788163b13f98ce7e2cc2d7943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/0014-5793(91)80604-2$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19697605$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2044765$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stockman, Brian J.</creatorcontrib><creatorcontrib>Nirmala, N.R.</creatorcontrib><creatorcontrib>Wagner, Gerhard</creatorcontrib><creatorcontrib>Delcamp, Tavner J.</creatorcontrib><creatorcontrib>DeYarman, Michael T.</creatorcontrib><creatorcontrib>Freisheim, James H.</creatorcontrib><title>Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy</title><title>FEBS letters</title><addtitle>FEBS Lett</addtitle><description>Dihydrofolate reductase (DHFR) is an intracellular target enzyme for folate antagonist drugs, including methotrexatte. In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation of the drug bound to human DHFR in solution. In agreement with what has been observed in the crystalline state, NOE's identified protein and methotrexate protons indicate that methotrexate binds in a non-productive orientation. In contrast to what has been reported for E. coli DHFR in solution, only one bound conformation of methotrexate is observed.</description><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>DHFR</subject><subject>dihydrofolate reductase</subject><subject>Dihydrofolate reductase, Protein NMR, Protein-drug interaction</subject><subject>double quantum filtered correlated spectroscopy</subject><subject>DQF-COSY</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Interactions. Associations</subject><subject>Intermolecular phenomena</subject><subject>Magnetic Resonance Spectroscopy - methods</subject><subject>Methotrexate</subject><subject>Methotrexate - metabolism</subject><subject>Molecular biophysics</subject><subject>NOE</subject><subject>NOESY</subject><subject>nuclear Overhauser enhancement</subject><subject>nuclear Overhauser enhancement spectroscopy</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Solutions</subject><subject>Tetrahydrofolate Dehydrogenase - chemistry</subject><subject>Tetrahydrofolate Dehydrogenase - metabolism</subject><issn>0014-5793</issn><issn>1873-3468</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU-LFDEQxYMo67j6DRRyURRszb9OOhdBlx0VdhVEzyGdVDORns5s0r06fnqTnWG9qaeQqt97SdVD6DElryih8jUhVDSt0vy5pi86Iolo2B20op3iDReyu4tWt8h99CDn76TcO6pP0AkjQijZrtCvS5g3cU7w086A-zD5jMOELZ7i1OxS9IubwzXgmAJMs51DnPAc8WbZ2gn7sNn7FIc4VnGCCtsM1SDHcanwS9yXisdF9unyC847cHOK2cXd_iG6N9gxw6PjeYq-rc-_nn1oLj6__3j29qJxQjDWOOIGL2zbekoHPjDSDp2iWkohreytFbyjPWNcdR2VvKd80J0DBcw55pUW_BQ9O_iWca4WyLPZhuxgHO0EccmmI62WTJJ_grTViijCCygOoCuj5ASD2aWwtWlvKDE1G1MXb-rijabmJhvDiuzJ0X_pt-BvRccwSv_psW-zs-OQ7ORC_uOtpVaSVG594H6EEfb_9bZZn79jtVHrmt5U64feHIygrP86QDLZlZgd-JBKTsbH8PeJfgOtb78L</recordid><startdate>19910603</startdate><enddate>19910603</enddate><creator>Stockman, Brian J.</creator><creator>Nirmala, N.R.</creator><creator>Wagner, Gerhard</creator><creator>Delcamp, Tavner J.</creator><creator>DeYarman, Michael T.</creator><creator>Freisheim, James H.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M81</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>19910603</creationdate><title>Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy</title><author>Stockman, Brian J. ; Nirmala, N.R. ; Wagner, Gerhard ; Delcamp, Tavner J. ; DeYarman, Michael T. ; Freisheim, James H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4422-c0cfd4a55d11f3f205f87196646a6baa4381b223788163b13f98ce7e2cc2d7943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>DHFR</topic><topic>dihydrofolate reductase</topic><topic>Dihydrofolate reductase, Protein NMR, Protein-drug interaction</topic><topic>double quantum filtered correlated spectroscopy</topic><topic>DQF-COSY</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Humans</topic><topic>Interactions. Associations</topic><topic>Intermolecular phenomena</topic><topic>Magnetic Resonance Spectroscopy - methods</topic><topic>Methotrexate</topic><topic>Methotrexate - metabolism</topic><topic>Molecular biophysics</topic><topic>NOE</topic><topic>NOESY</topic><topic>nuclear Overhauser enhancement</topic><topic>nuclear Overhauser enhancement spectroscopy</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>Solutions</topic><topic>Tetrahydrofolate Dehydrogenase - chemistry</topic><topic>Tetrahydrofolate Dehydrogenase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Stockman, Brian J.</creatorcontrib><creatorcontrib>Nirmala, N.R.</creatorcontrib><creatorcontrib>Wagner, Gerhard</creatorcontrib><creatorcontrib>Delcamp, Tavner J.</creatorcontrib><creatorcontrib>DeYarman, Michael T.</creatorcontrib><creatorcontrib>Freisheim, James H.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 3</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>FEBS letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Stockman, Brian J.</au><au>Nirmala, N.R.</au><au>Wagner, Gerhard</au><au>Delcamp, Tavner J.</au><au>DeYarman, Michael T.</au><au>Freisheim, James H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy</atitle><jtitle>FEBS letters</jtitle><addtitle>FEBS Lett</addtitle><date>1991-06-03</date><risdate>1991</risdate><volume>283</volume><issue>2</issue><spage>267</spage><epage>269</epage><pages>267-269</pages><issn>0014-5793</issn><eissn>1873-3468</eissn><coden>FEBLAL</coden><abstract>Dihydrofolate reductase (DHFR) is an intracellular target enzyme for folate antagonist drugs, including methotrexatte. In order to compare the binding of methotrexate to human DHFR in solution with that observed in the crystalline state, NMR spectroscopy has been used to determine the conformation of the drug bound to human DHFR in solution. In agreement with what has been observed in the crystalline state, NOE's identified protein and methotrexate protons indicate that methotrexate binds in a non-productive orientation. In contrast to what has been reported for E. coli DHFR in solution, only one bound conformation of methotrexate is observed.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>2044765</pmid><doi>10.1016/0014-5793(91)80604-2</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | FEBS letters, 1991-06, Vol.283 (2), p.267-269 |
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| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Binding Sites Biological and medical sciences DHFR dihydrofolate reductase Dihydrofolate reductase, Protein NMR, Protein-drug interaction double quantum filtered correlated spectroscopy DQF-COSY Fundamental and applied biological sciences. Psychology Humans Interactions. Associations Intermolecular phenomena Magnetic Resonance Spectroscopy - methods Methotrexate Methotrexate - metabolism Molecular biophysics NOE NOESY nuclear Overhauser enhancement nuclear Overhauser enhancement spectroscopy Protein Binding Protein Conformation Recombinant Proteins - chemistry Recombinant Proteins - metabolism Solutions Tetrahydrofolate Dehydrogenase - chemistry Tetrahydrofolate Dehydrogenase - metabolism |
| title | Methotrexate binds in a non-productive orientation to human dihydrofolate reductase in solution, based on NMR spectroscopy |
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