Human　multidrug　resistance　protein　1　(hMRP1)　is　an　important　member　of　the　ATP-binding　cassette　(ABC)　transporter　superfamily.　It　can　extrude　a　variety　of　anticancer　drugs　and　physiological　organic　anions　across　the　plasma　membrane,　which　is　activated　by　substrate　binding,　and　is　accompanied　by　large-scale　cooperative　movements　between　different　domains.　Currently,　it　remains　unclear　completely　about　how　the　specific　interactions　between　hMRP1　and　its　substrate　are　and　which　critical　residues　are　responsible　for　allosteric　signal　transduction.　To　the　end,　we　first　construct　an　inward-facing　state　of　hMRP1　using　homology　modeling　method,　and　then　dock　substrate　proinflammatory　agent　leukotriene　C4　(LTC4)　to　hMRP1　pocket.　The　result　manifests　LTC4　interacts　with　two　parts　of　hMRP1　pocket,　namely　the　positively　charged　pocket　(P　pocket)　and　hydrophobic　pocket　(H　pocket),　similar　to　its　binding　mode　with　bMRP1　(bovine　MRP1).　Additionally,　we　use　the　Gaussian　network　model　(GNM)-based　thermodynamic　method　proposed　by　us　to　identify　the　key　residues　whose　perturbations　markedly　alter　their　binding　free　energy.　Here　the　conventional　GNM　is　improved　with　covalent/non-covalent　interactions　and　secondary　structure　information　considered　(denoted　as　sscGNM).　In　the　result,　sscGNM　improves　the　flexibility　prediction,　especially　for　the　nucleotide　binding　domains　with　rich　kinds　of　secondary　structures.　The　46　key　residue　clusters　located　in　different　subdomains　are　identified　which　are　highly　consistent　with　experimental　observations.　Furtherly,　we　explore　the　long-range　cooperation　within　the　transporter.　This　study　is　helpful　for　strengthening　the　understanding　of　the　work　mechanism　in　ABC　exporters　and　can　provide　important　information　to　scientists　in　drug　design　studies.