Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition
SHP2 is a protein tyrosine phosphatase (PTP) that can regulate the tyrosine phosphorylation level. Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are...
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| Veröffentlicht in: | Molecular diversity 2022-06, Vol.26 (3), p.1567-1580 |
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| creator | Yangchun, Ma WenYu, Yang Liang, Zhou LiPeng, Li JingWei, Wu WeiYa, Li Shan, Du Ying, Ma RunLing, Wang |
| description | SHP2 is a protein tyrosine phosphatase (PTP) that can regulate the tyrosine phosphorylation level. Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are inhibitors of SHP2 and bind to different allosteric sites 1 and 2, respectively. Studies have shown that combining SHP099 with SHP844 will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamic simulations to explore the dual allosteric targeted inhibition mechanism. The result shows that the residues THR108-TRP112 (allosteric site 1) move to LEU236-GLN245 (αB-αC link loop in PTP domain) , the residues of GLN79-GLN87 (allosteric site 2) get close to LEU262-GLN269 (αA-αB link loop in PTP domain) and HIS458-ARG465 (P-loop) come near to ARG501-THR507 (Q-loop) in SHP2-SHP099-SHP844 system, which makes the “inactive conformation” more stable and prevents the substrate from entering the catalytic site. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2. |
| doi_str_mv | 10.1007/s11030-021-10286-4 |
| format | Article |
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Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are inhibitors of SHP2 and bind to different allosteric sites 1 and 2, respectively. Studies have shown that combining SHP099 with SHP844 will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamic simulations to explore the dual allosteric targeted inhibition mechanism. The result shows that the residues THR108-TRP112 (allosteric site 1) move to LEU236-GLN245 (αB-αC link loop in PTP domain) , the residues of GLN79-GLN87 (allosteric site 2) get close to LEU262-GLN269 (αA-αB link loop in PTP domain) and HIS458-ARG465 (P-loop) come near to ARG501-THR507 (Q-loop) in SHP2-SHP099-SHP844 system, which makes the “inactive conformation” more stable and prevents the substrate from entering the catalytic site. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2.</description><identifier>ISSN: 1381-1991</identifier><identifier>EISSN: 1573-501X</identifier><identifier>DOI: 10.1007/s11030-021-10286-4</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Binding sites ; Biochemistry ; Biomedical and Life Sciences ; Blood diseases ; Cancer therapies ; Drug therapy ; Hematology ; Kinases ; Laboratories ; Life Sciences ; Mutation ; Organic Chemistry ; Original Article ; Pharmacy ; Phosphatase ; Phosphorylation ; Polymer Sciences ; Proteins ; Signal transduction ; Tumors</subject><ispartof>Molecular diversity, 2022-06, Vol.26 (3), p.1567-1580</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021</rights><rights>The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-c70030091757eb2ae471afa3fe00ec0642969ecce9cf2f38ea376f051053f3983</citedby><cites>FETCH-LOGICAL-c396t-c70030091757eb2ae471afa3fe00ec0642969ecce9cf2f38ea376f051053f3983</cites><orcidid>0000-0001-7500-3423</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11030-021-10286-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11030-021-10286-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids></links><search><creatorcontrib>Yangchun, Ma</creatorcontrib><creatorcontrib>WenYu, Yang</creatorcontrib><creatorcontrib>Liang, Zhou</creatorcontrib><creatorcontrib>LiPeng, Li</creatorcontrib><creatorcontrib>JingWei, Wu</creatorcontrib><creatorcontrib>WeiYa, Li</creatorcontrib><creatorcontrib>Shan, Du</creatorcontrib><creatorcontrib>Ying, Ma</creatorcontrib><creatorcontrib>RunLing, Wang</creatorcontrib><title>Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition</title><title>Molecular diversity</title><addtitle>Mol Divers</addtitle><description>SHP2 is a protein tyrosine phosphatase (PTP) that can regulate the tyrosine phosphorylation level. Overexpression of SHP2 will promote the development of cancer diseases, so SHP2 has become one of the popular targets for the treatment of cancer. Studies have reported that both SHP099 and SHP844 are inhibitors of SHP2 and bind to different allosteric sites 1 and 2, respectively. Studies have shown that combining SHP099 with SHP844 will enhance pharmacological pathway inhibition in cells. This study uses molecular dynamic simulations to explore the dual allosteric targeted inhibition mechanism. The result shows that the residues THR108-TRP112 (allosteric site 1) move to LEU236-GLN245 (αB-αC link loop in PTP domain) , the residues of GLN79-GLN87 (allosteric site 2) get close to LEU262-GLN269 (αA-αB link loop in PTP domain) and HIS458-ARG465 (P-loop) come near to ARG501-THR507 (Q-loop) in SHP2-SHP099-SHP844 system, which makes the “inactive conformation” more stable and prevents the substrate from entering the catalytic site. Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2.</description><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Blood diseases</subject><subject>Cancer therapies</subject><subject>Drug therapy</subject><subject>Hematology</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Life Sciences</subject><subject>Mutation</subject><subject>Organic Chemistry</subject><subject>Original Article</subject><subject>Pharmacy</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Polymer Sciences</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Tumors</subject><issn>1381-1991</issn><issn>1573-501X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kcFKxDAQhosoqKsv4KngxUt1kjRNcxRRVxAUVPAWstnJNlKbNUlF397srqB48JQJ831DMn9RHBE4JQDiLBICDCqgpCJA26aqt4o9wgWrOJDn7VyzNrekJLvFfowvAFkjbK94v_xY9j64YVGmDkujx4ilt-vLfNR9qfvex4TBmTLpsMCE89INnZu55PxQ6pS06da6_81GlzCWOHR6MKvuw_Se_vIOih2r-4iH3-ekeLq6fLyYVrd31zcX57eVYbJJlRGQvwWSCC5wRjXWgmirmUUANNDUVDYSjUFpLLWsRc1EY4ET4Mwy2bJJcbKZuwz-bcSY1KuLBvteD-jHqCjngjPaEp7R4z_oix_DkF-naCNaLqSQkCm6oUzwMQa0ahncqw6fioBaRaE2UagchVpHoeossY0Ul6tNY_gZ_Y_1BX2mjNA</recordid><startdate>20220601</startdate><enddate>20220601</enddate><creator>Yangchun, Ma</creator><creator>WenYu, Yang</creator><creator>Liang, Zhou</creator><creator>LiPeng, Li</creator><creator>JingWei, Wu</creator><creator>WeiYa, Li</creator><creator>Shan, Du</creator><creator>Ying, Ma</creator><creator>RunLing, Wang</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7500-3423</orcidid></search><sort><creationdate>20220601</creationdate><title>Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition</title><author>Yangchun, Ma ; 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Meanwhile, residue GLU110 (allosteric site 1), ARG265 (allosteric site 2), and ARG501 (Q-loop) are speculated to be the key residues that causing the SHP2 protein in auto-inhibition conformation. It is hoped that this study will provide clues for the development of the dual allosteric targeted inhibition of SHP2.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><doi>10.1007/s11030-021-10286-4</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-7500-3423</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Binding sites Biochemistry Biomedical and Life Sciences Blood diseases Cancer therapies Drug therapy Hematology Kinases Laboratories Life Sciences Mutation Organic Chemistry Original Article Pharmacy Phosphatase Phosphorylation Polymer Sciences Proteins Signal transduction Tumors |
| title | Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition |
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