We have solved the structure of the Middle East Respiratory Syndrome coronavirus (MERS-CoV) papain-like protease (PLpro) to 1.8 Å resolution. The MERS-CoV PLpro blocking loop 2 (BL2) structure differs significantly from that of SARS-CoV PLpro, where it plays a crucial role in inhibitor binding.  Four previously designed SARS-CoV PLpro lead inhibitors with SARS-PLpro IC₅₀ values ranging from 0.2 to 2.0 µM were tested against MERS-CoV PLpro, with none of them effective against MERS-CoV PLpro.  Structure and sequence alignments demonstrated that two residues, Y269 and Q270, strongly responsible for inhibitor binding to SARS-CoV PLpro are replaced by T274 and A275 in MERS-CoV PLpro, eliminating critical binding interactions for similar types of inhibitors.  High-throughput screening (HTS) of 25,000 a compound library against both PLpro enzymes identified a small fragment-like non-covalent dual inhibitor.  This newly identified compound acts as a competitive inhibitor with an IC₅₀ of 6 µM against MERS-CoV PLpro, indicating that it binds to the active site, whereas it acts as an allosteric inhibitor against SARS-CoV PLpro with an IC₅₀ of 11 µM. Additionally, inhibitory activity of this compound was selective for SARS-CoV and MERS-CoV PLpro enzymes over two human homologues, the ubiquitin C-terminal hydrolases 1 and 3 (hUCH-L1 and hUCH-L3). These combined results demonstrate that inhibitor recognition specificity of MERS-CoV PLpro differs from that of SARS-CoV PLpro, and that promising inhibitor specificity can be obtained.