A three-dimensional construction of the active site (region 507–749) of human neutral endopeptidase (EC.3.4.24.11)
A three-dimensional model of the 507–749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of tw...
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| Veröffentlicht in: | Protein engineering 1999-02, Vol.12 (2), p.141-149 |
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| creator | Tiraboschi, Gilles Jullian, Nathalie Thery, Vincent Antonczak, Serge Fournie-Zaluski, Marie-Claude Roques, Bernard P. |
| description | A three-dimensional model of the 507–749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1′ subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper. |
| doi_str_mv | 10.1093/protein/12.2.141 |
| format | Article |
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Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1′ subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. 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Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1′ subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper.</description><subject>Amino Acid Sequence</subject><subject>Binding Sites</subject><subject>Cysteine - chemistry</subject><subject>disulfide bridge</subject><subject>enzyme active-site</subject><subject>enzyme inhibitor complex</subject><subject>homology modelling</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Kinetics</subject><subject>Matrix Metalloproteinase 3 - chemistry</subject><subject>Metalloendopeptidases - chemistry</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Neprilysin - chemistry</subject><subject>Protein Structure, Tertiary</subject><subject>S1′ subsite modeling</subject><subject>secondary structure prediction</subject><subject>sequence alignment</subject><subject>Sequence Alignment - methods</subject><subject>Sequence Homology, Amino Acid</subject><subject>structure refinement</subject><subject>Thermolysin - chemistry</subject><subject>thiorphan</subject><subject>Thiorphan - chemistry</subject><subject>zinc metallopeptidase</subject><issn>0269-2139</issn><issn>1741-0126</issn><issn>1460-213X</issn><issn>1741-0134</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhS1ERZfCnROKOCAqlNQe23F8rJaWIq2EkECquFheZ0JTNnGwHQQ3_kP_Ib-kXmWFECdOM6P53ju8R8gzRitGNT-bgk_Yj2cMKqiYYA_IiomalsD49UOyolDr_a6PyeMYbymlDdXwiBwzyrSERq5IOi_STUAs237AMfZ-tLvC-TGmMLuUz8J3mcDC5us7FrFPWLwK-GX_klT9_nWnhD7dUzfzYMdixDmF7IFj6yecUt_amBUX64pXogJRMXb6hBx1dhfx6WGekE-XFx_XV-Xm_dt36_NN6QSoVCpQDEE45qSVXHEF4BDcttEOXNPVqu64wLZlTtlaW96pjtKttcpyKhpQ_IS8XHxzTt9mjMkMfXS429kR_RwNUFHrhrIMvvgHvPVzyFFkBqRoqOQ6Q3SBXPAxBuzMFPrBhp-GUbOvwxzqMAwMmFxHljw_-M7bAdu_BEv-GXi9AH6e_seuXOg-Jvzxh7fhq6lzPNJcXX82cr15IyTn5gO_B5xaoyY</recordid><startdate>19990201</startdate><enddate>19990201</enddate><creator>Tiraboschi, Gilles</creator><creator>Jullian, Nathalie</creator><creator>Thery, Vincent</creator><creator>Antonczak, Serge</creator><creator>Fournie-Zaluski, Marie-Claude</creator><creator>Roques, Bernard P.</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</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>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope></search><sort><creationdate>19990201</creationdate><title>A three-dimensional construction of the active site (region 507–749) of human neutral endopeptidase (EC.3.4.24.11)</title><author>Tiraboschi, Gilles ; Jullian, Nathalie ; Thery, Vincent ; Antonczak, Serge ; Fournie-Zaluski, Marie-Claude ; Roques, Bernard P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-7271e24c1c5a5373722ce2cb89c2c8f676f34edd1c7a69a3f7f00baa7a3048273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Amino Acid Sequence</topic><topic>Binding Sites</topic><topic>Cysteine - chemistry</topic><topic>disulfide bridge</topic><topic>enzyme active-site</topic><topic>enzyme inhibitor complex</topic><topic>homology modelling</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Kinetics</topic><topic>Matrix Metalloproteinase 3 - chemistry</topic><topic>Metalloendopeptidases - chemistry</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Neprilysin - chemistry</topic><topic>Protein Structure, Tertiary</topic><topic>S1′ subsite modeling</topic><topic>secondary structure prediction</topic><topic>sequence alignment</topic><topic>Sequence Alignment - methods</topic><topic>Sequence Homology, Amino Acid</topic><topic>structure refinement</topic><topic>Thermolysin - chemistry</topic><topic>thiorphan</topic><topic>Thiorphan - chemistry</topic><topic>zinc metallopeptidase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tiraboschi, Gilles</creatorcontrib><creatorcontrib>Jullian, Nathalie</creatorcontrib><creatorcontrib>Thery, Vincent</creatorcontrib><creatorcontrib>Antonczak, Serge</creatorcontrib><creatorcontrib>Fournie-Zaluski, Marie-Claude</creatorcontrib><creatorcontrib>Roques, Bernard P.</creatorcontrib><collection>Istex</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>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Protein engineering</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tiraboschi, Gilles</au><au>Jullian, Nathalie</au><au>Thery, Vincent</au><au>Antonczak, Serge</au><au>Fournie-Zaluski, Marie-Claude</au><au>Roques, Bernard P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A three-dimensional construction of the active site (region 507–749) of human neutral endopeptidase (EC.3.4.24.11)</atitle><jtitle>Protein engineering</jtitle><stitle>Protein Eng</stitle><addtitle>Protein Eng</addtitle><date>1999-02-01</date><risdate>1999</risdate><volume>12</volume><issue>2</issue><spage>141</spage><epage>149</epage><pages>141-149</pages><issn>0269-2139</issn><issn>1741-0126</issn><eissn>1460-213X</eissn><eissn>1741-0134</eissn><abstract>A three-dimensional model of the 507–749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1′ subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>10195285</pmid><doi>10.1093/protein/12.2.141</doi><tpages>9</tpages></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals |
| subjects | Amino Acid Sequence Binding Sites Cysteine - chemistry disulfide bridge enzyme active-site enzyme inhibitor complex homology modelling Humans Inhibitory Concentration 50 Kinetics Matrix Metalloproteinase 3 - chemistry Metalloendopeptidases - chemistry Models, Molecular Molecular Sequence Data Neprilysin - chemistry Protein Structure, Tertiary S1′ subsite modeling secondary structure prediction sequence alignment Sequence Alignment - methods Sequence Homology, Amino Acid structure refinement Thermolysin - chemistry thiorphan Thiorphan - chemistry zinc metallopeptidase |
| title | A three-dimensional construction of the active site (region 507–749) of human neutral endopeptidase (EC.3.4.24.11) |
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