Porcine　reproductive　and　respiratory　syndrome　(PRRS)　has　become　an　economically　critical　factor　in　swine　industry　since　its　worldwide　spread　in　the　1990s.　Infection　by　its　causative　agent,　PRRS　virus　(PRRSV),　was　proven　to　be　mediated　by　an　indispensable　receptor,　porcine　CD163　(pCD163),　and　the　fifth　scavenger　receptor　cysteine-rich　domain　(SRCR5)　is　essential　for　virus　infection.　However,　the　structural　details　and　specific　residues　of　pCD163　SRCR5　involved　in　infection　have　not　been　defined　yet.　In　this　study,　we　prepared　recombinant　pCD163　SRCR5　in　Drosophila　melanogaster　Schneider　2　(S2)　cells　and　determined　its　crystal　structure　at　a　high　resolution　of　2.0　Å.　This　structure　includes　a　markedly　long　loop　region　and　shows　a　special　electrostatic　potential,　and　these　are　significantly　different　from　those　of　other　members　of　the　scavenger　receptor　cysteine-rich　superfamily　(SRCR-SF).　Subsequently,　we　carried　out　structure-based　mutational　studies　to　identify　that　the　arginine　residue　at　position　561　(Arg561)　in　the　long　loop　region　is　important　for　PRRSV　infection.　Further,　we　showed　Arg561　probably　takes　effect　on　the　binding　of　pCD163　to　PRRSV　during　virus　invasion.　Altogether　the　current　work　provides　the　first　view　of　the　CD163　SRCR　domain,　expands　our　knowledge　of　the　invasion　mechanism　of　PRRSV,　and　supports　a　molecular　basis　for　prevention　and　control　of　the　virus.　©　2017　American　Society　for　Microbiology.　All　Rights　Reserved.