Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations
P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafis...
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| creator | Huang, Li-Dong Fan, Ying-Zhe Tian, Yun Yang, Yang Liu, Yan Wang, Jin Zhao, Wen-Shan Zhou, Wen-Chao Cheng, Xiao-Yang Cao, Peng Lu, Xiang-Yang Yu, Ye |
| description | P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors. |
| doi_str_mv | 10.1371/journal.pone.0097528 |
| format | Article |
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Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0097528</identifier><identifier>PMID: 24878662</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accuracy ; Adenine ; Adenosine Triphosphate - metabolism ; Affinity labeling ; Affinity labelling ; Allosteric properties ; Allosteric Regulation ; Analysis ; Animals ; ATP ; Augmented reality ; Binding ; Binding Sites ; Biocompatibility ; Biology and Life Sciences ; Biomedical materials ; Biotechnology ; Bladder ; Chemical compounds ; Computer and Information Sciences ; Computer simulation ; Crystal structure ; Docking ; Dynamics ; Free energy ; Health aspects ; Huang, Ying ; Ion channels ; Ligands ; Medicine ; Modulators ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular modelling ; Movement ; Osteoporosis ; Pain ; Pharmacology ; Physical Sciences ; Physiological aspects ; Physiology ; Protein Structure, Tertiary ; Proteins ; Purines ; Receptors ; Receptors, Purinergic P2X4 - chemistry ; Receptors, Purinergic P2X4 - metabolism ; Recognition ; Residues ; Simulation ; Thermodynamics ; Urinary bladder ; Zebrafish ; Zebrafish Proteins - chemistry ; Zebrafish Proteins - metabolism</subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e97528-e97528</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Huang et al 2014 Huang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-90ce4f0ebc58fd8e4ffe03d44bed71a1a9455313d2d2b4a5cc0982e94add97083</citedby><cites>FETCH-LOGICAL-c692t-90ce4f0ebc58fd8e4ffe03d44bed71a1a9455313d2d2b4a5cc0982e94add97083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039465/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039465/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24878662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Li-Dong</creatorcontrib><creatorcontrib>Fan, Ying-Zhe</creatorcontrib><creatorcontrib>Tian, Yun</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Wang, Jin</creatorcontrib><creatorcontrib>Zhao, Wen-Shan</creatorcontrib><creatorcontrib>Zhou, Wen-Chao</creatorcontrib><creatorcontrib>Cheng, Xiao-Yang</creatorcontrib><creatorcontrib>Cao, Peng</creatorcontrib><creatorcontrib>Lu, Xiang-Yang</creatorcontrib><creatorcontrib>Yu, Ye</creatorcontrib><title>Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.</description><subject>Accuracy</subject><subject>Adenine</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Affinity labeling</subject><subject>Affinity labelling</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>Analysis</subject><subject>Animals</subject><subject>ATP</subject><subject>Augmented reality</subject><subject>Binding</subject><subject>Binding Sites</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>Biotechnology</subject><subject>Bladder</subject><subject>Chemical compounds</subject><subject>Computer and Information Sciences</subject><subject>Computer simulation</subject><subject>Crystal structure</subject><subject>Docking</subject><subject>Dynamics</subject><subject>Free energy</subject><subject>Health aspects</subject><subject>Huang, Ying</subject><subject>Ion channels</subject><subject>Ligands</subject><subject>Medicine</subject><subject>Modulators</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular modelling</subject><subject>Movement</subject><subject>Osteoporosis</subject><subject>Pain</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Purines</subject><subject>Receptors</subject><subject>Receptors, Purinergic P2X4 - chemistry</subject><subject>Receptors, Purinergic P2X4 - metabolism</subject><subject>Recognition</subject><subject>Residues</subject><subject>Simulation</subject><subject>Thermodynamics</subject><subject>Urinary bladder</subject><subject>Zebrafish</subject><subject>Zebrafish Proteins - chemistry</subject><subject>Zebrafish Proteins - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9-L1DAQx4so3rn6H4gGBNGHXfOrbeqDsBz-WDi4Q0_xLaTJtM3SNmvSqvfi3266u3fsyj1IHzJMPvOdyXQmSZ4SvCAsJ2_WbvS9ahcb18MC4yJPqbiXnJKC0XlGMbt_YJ8kj0JYY5wykWUPkxPKRR4tepr8WfUNeOgHZK571VkdkKtQA8og4zple6Sd99CqAQL6ZYcGLa8u5x60q3s7WNdP-CX9zlH0wWZwPrxFtg-2boaA6igABlXedahzLeixVR4F28VzCg6PkweVagM82Z-z5OuH91dnn-bnFx9XZ8vzuc4KOswLrIFXGEqdisqIaFeAmeG8BJMTRVTB05QRZqihJVep1rgQFAqujClyLNgseb7T3bQuyH3rgiQpwxmhOWWRWO0I49RabrztlL-WTlm5dThfS-UHq1uQmFR5SUShRak5p6kSCmgucKyCp1ksbJa822cbyw6Mju31qj0SPb7pbSNr91NyzAqepVHg1V7Aux8jhEF2NmhoW9WDG7d1kyLNmZjqfvEPevfr9lSt4gNsX7mYV0-icslJTrjI8JR2cQcVPwNxMuKcVTb6jwJeHwVEZoDfQ63GEOTqy-f_Zy--HbMvD9g4je3QBNeO25k5BvkO1N6F4KG6bTLBclqTm27IaU3kfk1i2LPDH3QbdLMX7C_JSQ51</recordid><startdate>20140530</startdate><enddate>20140530</enddate><creator>Huang, Li-Dong</creator><creator>Fan, Ying-Zhe</creator><creator>Tian, Yun</creator><creator>Yang, Yang</creator><creator>Liu, Yan</creator><creator>Wang, Jin</creator><creator>Zhao, Wen-Shan</creator><creator>Zhou, Wen-Chao</creator><creator>Cheng, Xiao-Yang</creator><creator>Cao, Peng</creator><creator>Lu, Xiang-Yang</creator><creator>Yu, Ye</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140530</creationdate><title>Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations</title><author>Huang, Li-Dong ; Fan, Ying-Zhe ; Tian, Yun ; Yang, Yang ; Liu, Yan ; Wang, Jin ; Zhao, Wen-Shan ; Zhou, Wen-Chao ; Cheng, Xiao-Yang ; Cao, Peng ; Lu, Xiang-Yang ; Yu, Ye</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-90ce4f0ebc58fd8e4ffe03d44bed71a1a9455313d2d2b4a5cc0982e94add97083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Accuracy</topic><topic>Adenine</topic><topic>Adenosine Triphosphate - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Li-Dong</au><au>Fan, Ying-Zhe</au><au>Tian, Yun</au><au>Yang, Yang</au><au>Liu, Yan</au><au>Wang, Jin</au><au>Zhao, Wen-Shan</au><au>Zhou, Wen-Chao</au><au>Cheng, Xiao-Yang</au><au>Cao, Peng</au><au>Lu, Xiang-Yang</au><au>Yu, Ye</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-05-30</date><risdate>2014</risdate><volume>9</volume><issue>5</issue><spage>e97528</spage><epage>e97528</epage><pages>e97528-e97528</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR) of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4) receptor reveal a large ATP-binding pocket (ABP) located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3) within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1), in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24878662</pmid><doi>10.1371/journal.pone.0097528</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e97528-e97528 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1530612723 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Accuracy Adenine Adenosine Triphosphate - metabolism Affinity labeling Affinity labelling Allosteric properties Allosteric Regulation Analysis Animals ATP Augmented reality Binding Binding Sites Biocompatibility Biology and Life Sciences Biomedical materials Biotechnology Bladder Chemical compounds Computer and Information Sciences Computer simulation Crystal structure Docking Dynamics Free energy Health aspects Huang, Ying Ion channels Ligands Medicine Modulators Molecular Docking Simulation Molecular Dynamics Simulation Molecular modelling Movement Osteoporosis Pain Pharmacology Physical Sciences Physiological aspects Physiology Protein Structure, Tertiary Proteins Purines Receptors Receptors, Purinergic P2X4 - chemistry Receptors, Purinergic P2X4 - metabolism Recognition Residues Simulation Thermodynamics Urinary bladder Zebrafish Zebrafish Proteins - chemistry Zebrafish Proteins - metabolism |
| title | Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations |
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