... and then employee me! I design systems like this all day every day!
The first question is .... how much budget can you cost justify? Remember the only rules in big system design are time/money/rules of physics/justification
Now you can design your system.
... and now I'm going to help you cheat .... speak to these guys! SQLCAT .... 50k users is nothing, they've helped design Microsoft.com, Bing.com and MySpace.com all with just afew more users every minute!