Structural modeling of osteoarthritis ADAMTS4 complex with its cognate inhibitory protein TIMP3 and rational derivation of cyclic peptide inhibitors from the complex interface to target ADAMTS4

[Display omitted] •An inhibitory loop peptide at ADAMTS4–TIMP3 complex interface is derived to target osteoarthritis ADAMTS4.•A cyclization strategy is described to improve the loop peptide affinity by minimizing entropy penalty.•Cyclization can promote nonbonded interactions by restricting free pep...

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Veröffentlicht in:Bioorganic chemistry 2018-02, Vol.76, p.13-22
Hauptverfasser: Zhang, Wei, Zhong, Biao, Zhang, Chi, Wang, Yukai, Guo, Shang, Luo, Congfeng, Zhan, Yulin
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container_issue
container_start_page 13
container_title Bioorganic chemistry
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creator Zhang, Wei
Zhong, Biao
Zhang, Chi
Wang, Yukai
Guo, Shang
Luo, Congfeng
Zhan, Yulin
description [Display omitted] •An inhibitory loop peptide at ADAMTS4–TIMP3 complex interface is derived to target osteoarthritis ADAMTS4.•A cyclization strategy is described to improve the loop peptide affinity by minimizing entropy penalty.•Cyclization can promote nonbonded interactions by restricting free peptides into their active conformation.•Binding analysis confirms that the affinity of cyclic peptides increases by 3–9-fold relative to their linear counterparts. The ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) enzyme is a matrix-associated zinc metalloendopeptidase that plays an essential role in the degradation of cartilage aggrecan in arthritic diseases and has been recognized as one of the most primary targets for therapeutic intervention in osteoarthritis (OA). Here, we reported computational modeling of the atomic-level complex structure of ADAMTS4 with its cognate inhibitory protein TIMP3 based on high-resolution crystal template. By systematically examining the modeled complex structure we successfully identified a short inhibitory loop (62EASESLC68) in TIMP3 N-terminal inhibitory domain (NID) that directly participates in blocking the enzyme’s active site, which, and its extended versions, were then broken from the full-length protein to serve as the peptide inhibitor candidates of ADAMTS4. Atomistic molecular dynamics simulation, binding energetic analysis, and fluorescence-based assay revealed that the TIMP3-derived linear peptides can only bind weakly to the enzyme (Kd = 74 ± 8 μM), which would incur a considerable entropy penalty due to the high conformational flexibility and intrinsic disorder of these linear peptides. In this respect, we proposed a cyclization strategy to improve enzyme–peptide binding affinity by, instead of traditionally maximizing enthalpy contribution, minimizing entropy cost of the binding, where a disulfide bond was added across the two terminal residues of linear peptides, resulting in a number of TIMP3-derived cyclic peptides. Our studies confirmed that the cyclization, as might be expected, can promote peptide binding capability against ADAMTS4 substantially, with affinity increase by 3-fold, 9-fold and 7-fold for cyclic peptides ▪, ▪ and ▪, respectively.
doi_str_mv 10.1016/j.bioorg.2017.10.017
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The ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) enzyme is a matrix-associated zinc metalloendopeptidase that plays an essential role in the degradation of cartilage aggrecan in arthritic diseases and has been recognized as one of the most primary targets for therapeutic intervention in osteoarthritis (OA). Here, we reported computational modeling of the atomic-level complex structure of ADAMTS4 with its cognate inhibitory protein TIMP3 based on high-resolution crystal template. By systematically examining the modeled complex structure we successfully identified a short inhibitory loop (62EASESLC68) in TIMP3 N-terminal inhibitory domain (NID) that directly participates in blocking the enzyme’s active site, which, and its extended versions, were then broken from the full-length protein to serve as the peptide inhibitor candidates of ADAMTS4. Atomistic molecular dynamics simulation, binding energetic analysis, and fluorescence-based assay revealed that the TIMP3-derived linear peptides can only bind weakly to the enzyme (Kd = 74 ± 8 μM), which would incur a considerable entropy penalty due to the high conformational flexibility and intrinsic disorder of these linear peptides. In this respect, we proposed a cyclization strategy to improve enzyme–peptide binding affinity by, instead of traditionally maximizing enthalpy contribution, minimizing entropy cost of the binding, where a disulfide bond was added across the two terminal residues of linear peptides, resulting in a number of TIMP3-derived cyclic peptides. 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The ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) enzyme is a matrix-associated zinc metalloendopeptidase that plays an essential role in the degradation of cartilage aggrecan in arthritic diseases and has been recognized as one of the most primary targets for therapeutic intervention in osteoarthritis (OA). Here, we reported computational modeling of the atomic-level complex structure of ADAMTS4 with its cognate inhibitory protein TIMP3 based on high-resolution crystal template. By systematically examining the modeled complex structure we successfully identified a short inhibitory loop (62EASESLC68) in TIMP3 N-terminal inhibitory domain (NID) that directly participates in blocking the enzyme’s active site, which, and its extended versions, were then broken from the full-length protein to serve as the peptide inhibitor candidates of ADAMTS4. Atomistic molecular dynamics simulation, binding energetic analysis, and fluorescence-based assay revealed that the TIMP3-derived linear peptides can only bind weakly to the enzyme (Kd = 74 ± 8 μM), which would incur a considerable entropy penalty due to the high conformational flexibility and intrinsic disorder of these linear peptides. In this respect, we proposed a cyclization strategy to improve enzyme–peptide binding affinity by, instead of traditionally maximizing enthalpy contribution, minimizing entropy cost of the binding, where a disulfide bond was added across the two terminal residues of linear peptides, resulting in a number of TIMP3-derived cyclic peptides. Our studies confirmed that the cyclization, as might be expected, can promote peptide binding capability against ADAMTS4 substantially, with affinity increase by 3-fold, 9-fold and 7-fold for cyclic peptides ▪, ▪ and ▪, respectively.</description><subject>ADAMTS4</subject><subject>ADAMTS4 Protein - chemistry</subject><subject>ADAMTS4 Protein - metabolism</subject><subject>Binding Sites</subject><subject>Conformational flexibility</subject><subject>Cyclization</subject><subject>Entropy</subject><subject>Entropy penalty</subject><subject>Humans</subject><subject>Molecular Dynamics Simulation</subject><subject>Osteoarthritis</subject><subject>Peptide</subject><subject>Peptide Fragments - chemical synthesis</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptides, Cyclic - chemical synthesis</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Protein Binding</subject><subject>Protein Domains</subject><subject>Tissue Inhibitor of Metalloproteinase-3 - chemical synthesis</subject><subject>Tissue Inhibitor of Metalloproteinase-3 - chemistry</subject><subject>Tissue Inhibitor of Metalloproteinase-3 - metabolism</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1v1DAQjRCILoV_gJCPXLLYjvOxF6RVgVKpFUhdzpZjT3ZnlcTBnhT25_HP6mXbihOnp3l6M29mXpa9FXwpuKg-7Jcteh-2S8lFnahlgmfZQvAVz6WQ_Hm24FyVueRVc5a9inHPuRCqrl5mZ3IluKxlucj-3FKYLc3B9GzwDnoct8x3zEcCbwLtAhJGtv60vtncKmb9MPXwm_1C2jGkmIjtaAgYjjtskXw4sCl4AhzZ5urme8HM6FgwhH5MDg4C3v0tjh72YHu0bIKJ0P0zIrIu-IHRDp78cCQInbHAyDMyYQv0uNPr7EVn-ghvHvA8-_Hl8-bia3797fLqYn2d26JpKG9to2RpatVUZSUdTw9oK-ekKGsnrZTSlKUCZW1hK5BFLUTNG2isqIpCSq6K8-z9aW667-cMkfSA0ULfmxH8HLVYVYInrZJJqk5SG3yMATo9BRxMOGjB9TE8vden8PQxvCObILW9e3CY2wHcU9NjWknw8SSAdOcdQtDRIowWHAawpJ3H_zvcA1Jir0c</recordid><startdate>20180201</startdate><enddate>20180201</enddate><creator>Zhang, Wei</creator><creator>Zhong, Biao</creator><creator>Zhang, Chi</creator><creator>Wang, Yukai</creator><creator>Guo, Shang</creator><creator>Luo, Congfeng</creator><creator>Zhan, Yulin</creator><general>Elsevier Inc</general><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>7X8</scope></search><sort><creationdate>20180201</creationdate><title>Structural modeling of osteoarthritis ADAMTS4 complex with its cognate inhibitory protein TIMP3 and rational derivation of cyclic peptide inhibitors from the complex interface to target ADAMTS4</title><author>Zhang, Wei ; Zhong, Biao ; Zhang, Chi ; Wang, Yukai ; Guo, Shang ; Luo, Congfeng ; Zhan, Yulin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-bc8425a7486562d0102b6dd2157d2c222a554e4cc3c6e23711708e8c163322043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>ADAMTS4</topic><topic>ADAMTS4 Protein - chemistry</topic><topic>ADAMTS4 Protein - metabolism</topic><topic>Binding Sites</topic><topic>Conformational flexibility</topic><topic>Cyclization</topic><topic>Entropy</topic><topic>Entropy penalty</topic><topic>Humans</topic><topic>Molecular Dynamics Simulation</topic><topic>Osteoarthritis</topic><topic>Peptide</topic><topic>Peptide Fragments - chemical synthesis</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptides, Cyclic - chemical synthesis</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - metabolism</topic><topic>Protein Binding</topic><topic>Protein Domains</topic><topic>Tissue Inhibitor of Metalloproteinase-3 - chemical synthesis</topic><topic>Tissue Inhibitor of Metalloproteinase-3 - chemistry</topic><topic>Tissue Inhibitor of Metalloproteinase-3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Zhong, Biao</creatorcontrib><creatorcontrib>Zhang, Chi</creatorcontrib><creatorcontrib>Wang, Yukai</creatorcontrib><creatorcontrib>Guo, Shang</creatorcontrib><creatorcontrib>Luo, Congfeng</creatorcontrib><creatorcontrib>Zhan, Yulin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Wei</au><au>Zhong, Biao</au><au>Zhang, Chi</au><au>Wang, Yukai</au><au>Guo, Shang</au><au>Luo, Congfeng</au><au>Zhan, Yulin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural modeling of osteoarthritis ADAMTS4 complex with its cognate inhibitory protein TIMP3 and rational derivation of cyclic peptide inhibitors from the complex interface to target ADAMTS4</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2018-02-01</date><risdate>2018</risdate><volume>76</volume><spage>13</spage><epage>22</epage><pages>13-22</pages><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted] •An inhibitory loop peptide at ADAMTS4–TIMP3 complex interface is derived to target osteoarthritis ADAMTS4.•A cyclization strategy is described to improve the loop peptide affinity by minimizing entropy penalty.•Cyclization can promote nonbonded interactions by restricting free peptides into their active conformation.•Binding analysis confirms that the affinity of cyclic peptides increases by 3–9-fold relative to their linear counterparts. The ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) enzyme is a matrix-associated zinc metalloendopeptidase that plays an essential role in the degradation of cartilage aggrecan in arthritic diseases and has been recognized as one of the most primary targets for therapeutic intervention in osteoarthritis (OA). Here, we reported computational modeling of the atomic-level complex structure of ADAMTS4 with its cognate inhibitory protein TIMP3 based on high-resolution crystal template. By systematically examining the modeled complex structure we successfully identified a short inhibitory loop (62EASESLC68) in TIMP3 N-terminal inhibitory domain (NID) that directly participates in blocking the enzyme’s active site, which, and its extended versions, were then broken from the full-length protein to serve as the peptide inhibitor candidates of ADAMTS4. Atomistic molecular dynamics simulation, binding energetic analysis, and fluorescence-based assay revealed that the TIMP3-derived linear peptides can only bind weakly to the enzyme (Kd = 74 ± 8 μM), which would incur a considerable entropy penalty due to the high conformational flexibility and intrinsic disorder of these linear peptides. In this respect, we proposed a cyclization strategy to improve enzyme–peptide binding affinity by, instead of traditionally maximizing enthalpy contribution, minimizing entropy cost of the binding, where a disulfide bond was added across the two terminal residues of linear peptides, resulting in a number of TIMP3-derived cyclic peptides. Our studies confirmed that the cyclization, as might be expected, can promote peptide binding capability against ADAMTS4 substantially, with affinity increase by 3-fold, 9-fold and 7-fold for cyclic peptides ▪, ▪ and ▪, respectively.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29102725</pmid><doi>10.1016/j.bioorg.2017.10.017</doi><tpages>10</tpages></addata></record>
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subjects ADAMTS4
ADAMTS4 Protein - chemistry
ADAMTS4 Protein - metabolism
Binding Sites
Conformational flexibility
Cyclization
Entropy
Entropy penalty
Humans
Molecular Dynamics Simulation
Osteoarthritis
Peptide
Peptide Fragments - chemical synthesis
Peptide Fragments - chemistry
Peptide Fragments - metabolism
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - metabolism
Protein Binding
Protein Domains
Tissue Inhibitor of Metalloproteinase-3 - chemical synthesis
Tissue Inhibitor of Metalloproteinase-3 - chemistry
Tissue Inhibitor of Metalloproteinase-3 - metabolism
title Structural modeling of osteoarthritis ADAMTS4 complex with its cognate inhibitory protein TIMP3 and rational derivation of cyclic peptide inhibitors from the complex interface to target ADAMTS4
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