Quercetin　is　a　member　of　the　flavonoids　and　was　previously　demonstrated　to　inhibit　trypsin-like　serine　proteases　at　micromolar　potencies.　Different　molecular　models　were　proposed　to　explain　such　inhibition.　However,　controversies　remain　on　the　molecular　details　of　inhibition.　Here,　we　report　the　X-ray　crystal　structure　of　quercetin　in　a　complex　with　the　urokinase-type　plasminogen　activator　(uPA),　an　archetypical　serine　protease.　The　structure　showed　that　quercetin　binds　to　the　specific　substrate　binding　pocket　(S1　pocket)　of　uPA　mainly　through　its　two　neighboring　phenolic　hydroxyl　groups.　Our　study　thus　provides　unambiguous　evidence　to　support　quercetin　binding　to　serine　proteases　and　defines　the　molecular　basis　of　the　interaction.　Our　results　further　establish　that　natural　products　with　two　adjacent　phenolic　hydroxyl　groups　(or　catechol)　are　likely　to　inhibit　other　trypsin-like　serine　proteases,　a　new　mechanism　formerly　under-recognized.