Porcine　reproductive　and　respiratory　syndrome　(PRRS)　is　a　serious　disease　burdening　global　swine　industry.　Infection　by　its　etiological　agent,　PRRS　virus　(PRRSV),　shows　a　highly　restricted　tropism　of　host　cells　and　has　been　demonstrated　to　be　mediated　by　an　essential　scavenger　receptor　(SR)　CD163.　CD163　fifth　SR　cysteine-rich　domain　(SRCR5)　is　further　proven　to　play　a　crucial　role　during　viral　infection.　Despite　intense　research,　the　involvement　of　CD163　SRCR5　in　PRRSV　infection　remains　to　be　elucidated.　In　the　current　study,　we　prepared　recombinant　monkey　CD163　(moCD163)　SRCR5　and　human　CD163-like　homolog　(hCD163L1)　SRCR8,　and　determined　their　crystal　structures.　After　comparison　with　the　previously　reported　crystal　structure　of　porcine　CD163　(pCD163)　SRCR5,　these　structures　showed　almost　identical　structural　folds　but　significantly　different　surface　electrostatic　potentials.　Based　on　these　differences,　we　carried　out　mutational　research　to　identify　that　the　charged　residue　at　position　534　in　association　with　the　one　at　position　561　were　important　for　PRRSV-2　infection　in　vitro.　Altogether　the　current　work　sheds　some　light　on　CD163-mediated　PRRSV-2　infection　and　deepens　our　understanding　of　the　viral　pathogenesis,　which　will　provide　clues　for　prevention　and　control　of　PRRS.